Picolinamide compounds with fungicidal activity

ABSTRACT

This disclosure relates to picolinamides of Formula I and their use as fungicides.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. Nos. 62/098,120 filed Dec. 30, 2014 and 62/098,122filed Dec. 30, 2014, which are expressly incorporated by referenceherein.

BACKGROUND & SUMMARY

Fungicides are compounds, of natural or synthetic origin, which act toprotect and/or cure plants against damage caused by agriculturallyrelevant fungi. Generally, no single fungicide is useful in allsituations. Consequently, research is ongoing to produce fungicides thatmay have better performance, are easier to use, and cost less.

The present disclosure relates to picolinamides and their use asfungicides. The compounds of the present disclosure may offer protectionagainst ascomycetes, basidiomycetes, deuteromycetes and oomycetes.

One embodiment of the present disclosure may include compounds ofFormula I:

in which: X is hydrogen or C(O)R₅;

Y is hydrogen, C(O)R₅, or Q;

Q is

wherein: Z is N or CH;

R₁ is hydrogen or alkyl, each optionally substituted with 0, 1 ormultiple R₈;

R₂ is methyl;

R₃ is chosen from aryl or heteroaryl, each optionally substituted with0, 1 or multiple R₈;

R₄ is chosen from hydrogen, halo, hydroxyl, alkyl or alkoxy;

R₅ is chosen from alkoxy or benzyloxy, each optionally substituted with0, 1, or multiple R₈;

R₆ is chosen from hydrogen, alkoxy, or halo, each optionally substitutedwith 0, 1, or multiple R₈;

R₇ is chosen from hydrogen, —C(O)R₉, or —CH₂OC(O)R₉;

R₈ is chosen from hydrogen, alkyl, aryl, acyl, halo, alkenyl, alkynyl,alkoxy, cyano or heterocyclyl, each optionally substituted with 0, 1, ormultiple R₁₀:

R₉ is chosen from alkyl, alkoxy, or aryl, each optionally substitutedwith 0, 1, or multiple R₈;

R₁₀ is chosen from hydrogen, alkyl, aryl, acyl, halo, alkenyl, alkoxy,or heterocyclyl;

R₁₁ is chosen from hydrogen or alkyl, substituted with 0, 1, or multipleR₈;

R₁₂ is chosen from aryl or heteroaryl, each optionally substituted with0, 1 or multiple R₈.

Another embodiment of the present disclosure may include a fungicidalcomposition for the control or prevention of fungal attack comprisingthe compounds described above and a phytologically acceptable carriermaterial.

Yet another embodiment of the present disclosure may include a methodfor the control or prevention of fungal attack on a plant, the methodincluding the steps of applying a fungicidally effective amount of oneor more of the compounds described above to at least one of the fungus,the plant, and an area adjacent to the plant.

It will be understood by those skilled in the art that the followingterms may include generic “R”-groups within their definitions, e.g.,“the term alkoxy refers to an —OR substituent”. It is also understoodthat within the definitions for the following terms, these “R” groupsare included for illustration purposes and should not be construed aslimiting or being limited by substitutions about Formula I.

The term “alkyl” refers to a branched, unbranched, or saturated cycliccarbon chain, including, but not limited to, methyl, ethyl, propyl,butyl, isopropyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term “alkenyl” refers to a branched, unbranched or cyclic carbonchain containing one or more double bonds including, but not limited to,ethenyl, propenyl, butenyl, isopropenyl, isobutenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, and the like.

The term “alkynyl” refers to a branched or unbranched carbon chaincontaining one or more triple bonds including, but not limited to,propynyl, butynyl, and the like.

The terms “aryl” and “Ar” refer to any aromatic ring, mono- orbi-cyclic, containing 0 heteroatoms.

The term “heterocyclyl” refers to any aromatic or non-aromatic ring,mono- or bi-cyclic, containing one or more heteroatoms.

The term “alkoxy” refers to an —OR substituent.

The term “acyloxy” refers to an —OC(O)R substituent.

The term “cyano” refers to a —C≡N substituent.

The term “hydroxyl” refers to an —OH substituent.

The term “amino” refers to a —N(R)₂ substituent.

The term “arylalkoxy” refers to —O(CH₂)_(n)Ar where n is an integerselected from the list 1, 2, 3, 4, 5, or 6.

The term “haloalkoxy” refers to an —OR—X substituent, wherein X is Cl,F, Br, or I, or any combination thereof.

The term “haloalkyl” refers to an alkyl, which is substituted with Cl,F, I, or Br or any combination thereof.

The term “halogen” or “halo” refers to one or more halogen atoms,defined as F, Cl, Br, and I.

The term “nitro” refers to a —NO₂ substituent.

The term thioalkyl refers to an —SR substituent.

Throughout the disclosure, reference to the compounds of Formula I isread as also including all stereoisomers, for example diastereomers,enantiomers, and mixtures thereof. In another embodiment, Formula I isread as also including salts or hydrates thereof. Exemplary saltsinclude, but are not limited to: hydrochloride, hydrobromide,hydroiodide, trifluoroacetate, and trifluoromethane sulfonate.

It is also understood by those skilled in the art that additionalsubstitution is allowable, unless otherwise noted, as long as the rulesof chemical bonding and strain energy are satisfied and the productstill exhibits fungicidal activity.

Another embodiment of the present disclosure is a use of a compound ofFormula I, for protection of a plant against attack by a phytopathogenicorganism or the treatment of a plant infested by a phytopathogenicorganism, comprising the application of a compound of Formula I, or acomposition comprising the compound to soil, a plant, a part of a plant,foliage, and/or roots.

Additionally, another embodiment of the present disclosure is acomposition useful for protecting a plant against attack by aphytopathogenic organism and/or treatment of a plant infested by aphytopathogenic organism comprising a compound of Formula I and aphytologically acceptable carrier material.

DETAILED DESCRIPTION

The compounds of the present disclosure may be applied by any of avariety of known techniques, either as the compounds or as formulationscomprising the compounds. For example, the compounds may be applied tothe roots or foliage of plants for the control of various fungi, withoutdamaging the commercial value of the plants. The materials may beapplied in the form of any of the generally used formulation types, forexample, as solutions, dusts, wettable powders, flowable concentrate, oremulsifiable concentrates.

Preferably, the compounds of the present disclosure are applied in theform of a formulation, comprising one or more of the compounds ofFormula I with a phytologically acceptable carrier. Concentratedformulations may be dispersed in water, or other liquids, forapplication, or formulations may be dust-like or granular, which maythen be applied without further treatment. The formulations can beprepared according to procedures that are conventional in theagricultural chemical art.

The present disclosure contemplates all vehicles by which one or more ofthe compounds may be formulated for delivery and use as a fungicide.Typically, formulations are applied as aqueous suspensions or emulsions.Such suspensions or emulsions may be produced from water-soluble,water-suspendable, or emulsifiable formulations which are solids,usually known as wettable powders; or liquids, usually known asemulsifiable concentrates, aqueous suspensions, or suspensionconcentrates. As will be readily appreciated, any material to whichthese compounds may be added may be used, provided it yields the desiredutility without significant interference with the activity of thesecompounds as antifungal agents.

Wettable powders, which may be compacted to form water-dispersiblegranules, comprise an intimate mixture of one or more of the compoundsof Formula I, an inert carrier and surfactants. The concentration of thecompound in the wettable powder may be from about 10 percent to about 90percent by weight based on the total weight of the wettable powder, morepreferably about 25 weight percent to about 75 weight percent. In thepreparation of wettable powder formulations, the compounds may becompounded with any finely divided solid, such as prophyllite, talc,chalk, gypsum, Fuller's earth, bentonite, attapulgite, starch, casein,gluten, montmorillonite clays, diatomaceous earths, purified silicatesor the like. In such operations, the finely divided carrier andsurfactants are typically blended with the compound(s) and milled.

Emulsifiable concentrates of the compounds of Formula I may comprise aconvenient concentration, such as from about 1 weight percent to about50 weight percent of the compound, in a suitable liquid, based on thetotal weight of the concentrate. The compounds may be dissolved in aninert carrier, which is either a water-miscible solvent or a mixture ofwater-immiscible organic solvents, and emulsifiers. The concentrates maybe diluted with water and oil to form spray mixtures in the form ofoil-in-water emulsions. Useful organic solvents include aromatics,especially the high-boiling naphthalenic and olefinic portions ofpetroleum such as heavy aromatic naphtha. Other organic solvents mayalso be used, for example, terpenic solvents, including rosinderivatives, aliphatic ketones, such as cyclohexanone, and complexalcohols, such as 2-ethoxyethanol.

Emulsifiers which may be advantageously employed herein may be readilydetermined by those skilled in the art and include various nonionic,anionic, cationic and amphoteric emulsifiers, or a blend of two or moreemulsifiers. Examples of nonionic emulsifiers useful in preparing theemulsifiable concentrates include the polyalkylene glycol ethers andcondensation products of alkyl and aryl phenols, aliphatic alcohols,aliphatic amines or fatty acids with ethylene oxide, propylene oxidessuch as the ethoxylated alkyl phenols and carboxylic esters solubilizedwith the polyol or polyoxyalkylene. Cationic emulsifiers includequaternary ammonium compounds and fatty amine salts. Anionic emulsifiersinclude the oil-soluble salts (e.g., calcium) of alkylaryl sulfonicacids, oil-soluble salts or sulfated polyglycol ethers and appropriatesalts of phosphated polyglycol ether.

Representative organic liquids which may be employed in preparing theemulsifiable concentrates of the compounds of the present disclosure arethe aromatic liquids such as xylene, propyl benzene fractions; or mixednaphthalene fractions, mineral oils, substituted aromatic organicliquids such as dioctyl phthalate; kerosene; dialkyl amides of variousfatty acids, particularly the dimethyl amides of fatty glycols andglycol derivatives such as the n-butyl ether, ethyl ether or methylether of diethylene glycol, the methyl ether of triethylene glycol,petroleum fractions or hydrocarbons such as mineral oil, aromaticsolvents, paraffinic oils, and the like; vegetable oils such as soybeanoil, rapeseed oil, olive oil, castor oil, sunflower seed oil, coconutoil, corn oil, cottonseed oil, linseed oil, palm oil, peanut oil,safflower oil, sesame oil, tung oil and the like; esters of the abovevegetable oils; and the like. Mixtures of two or more organic liquidsmay also be employed in the preparation of the emulsifiable concentrate.Organic liquids include xylene, and propyl benzene fractions, withxylene being most preferred in some cases. Surface-active dispersingagents are typically employed in liquid formulations and in an amount offrom 0.1 to 20 percent by weight based on the combined weight of thedispersing agent with one or more of the compounds. The formulations canalso contain other compatible additives, for example, plant growthregulators and other biologically active compounds used in agriculture.

Aqueous suspensions comprise suspensions of one or more water-insolublecompounds of Formula I, dispersed in an aqueous vehicle at aconcentration in the range from about 1 to about 50 weight percent,based on the total weight of the aqueous suspension. Suspensions areprepared by finely grinding one or more of the compounds, and vigorouslymixing the ground material into a vehicle comprised of water andsurfactants chosen from the same types discussed above. Othercomponents, such as inorganic salts and synthetic or natural gums, mayalso be added to increase the density and viscosity of the aqueousvehicle.

The compounds of Formula I can also be applied as granular formulations,which are particularly useful for applications to the soil. Granularformulations generally contain from about 0.5 to about 10 weightpercent, based on the total weight of the granular formulation of thecompound(s), dispersed in an inert carrier which consists entirely or inlarge part of coarsely divided inert material such as attapulgite,bentonite, diatomite, clay or a similar inexpensive substance. Suchformulations are usually prepared by dissolving the compounds in asuitable solvent and applying it to a granular carrier which has beenpreformed to the appropriate particle size, in the range of from about0.5 to about 3 mm. A suitable solvent is a solvent in which the compoundis substantially or completely soluble. Such formulations may also beprepared by making a dough or paste of the carrier and the compound andsolvent, and crushing and drying to obtain the desired granularparticle.

Dusts containing the compounds of Formula I may be prepared byintimately mixing one or more of the compounds in powdered form with asuitable dusty agricultural carrier, such as, for example, kaolin clay,ground volcanic rock, and the like. Dusts can suitably contain fromabout 1 to about 10 weight percent of the compounds, based on the totalweight of the dust.

The formulations may additionally contain adjuvant surfactants toenhance deposition, wetting, and penetration of the compounds onto thetarget crop and organism. These adjuvant surfactants may optionally beemployed as a component of the formulation or as a tank mix. The amountof adjuvant surfactant will typically vary from 0.01 to 1.0 percent byvolume, based on a spray-volume of water, preferably 0.05 to 0.5 volumepercent. Suitable adjuvant surfactants include, but are not limited toethoxylated nonyl phenols, ethoxylated synthetic or natural alcohols,salts of the esters or sulfosuccinic acids, ethoxylated organosilicones,ethoxylated fatty amines, blends of surfactants with mineral orvegetable oils, crop oil concentrate (mineral oil (85%)+emulsifiers(15%)); nonylphenol ethoxylate; benzylcocoalkyldimethyl quaternaryammonium salt; blend of petroleum hydrocarbon, alkyl esters, organicacid, and anionic surfactant; C₉-C₁₁ alkylpolyglycoside; phosphatedalcohol ethoxylate; natural primary alcohol (C₁₂-C₁₆) ethoxylate;di-sec-butylphenol EO-PO block copolymer; polysiloxane-methyl cap;nonylphenol ethoxylate+urea ammonium nitrrate; emulsified methylatedseed oil; tridecyl alcohol (synthetic) ethoxylate (8EO); tallow amineethoxylate (15 EO); PEG(400) dioleate-99. The formulations may alsoinclude oil-in-water emulsions such as those disclosed in U.S. patentapplication Ser. No. 11/495,228, the disclosure of which is expresslyincorporated by reference herein.

The formulations may optionally include combinations that contain otherpesticidal compounds. Such additional pesticidal compounds may befungicides, insecticides, herbicides, nematocides, miticides,arthropodicides, bactericides or combinations thereof that arecompatible with the compounds of the present disclosure in the mediumselected for application, and not antagonistic to the activity of thepresent compounds. Accordingly, in such embodiments, the otherpesticidal compound is employed as a supplemental toxicant for the sameor for a different pesticidal use. The compounds of Formula I and thepesticidal compound in the combination can generally be present in aweight ratio of from 1:100 to 100:1.

The compounds of the present disclosure may also be combined with otherfungicides to form fungicidal mixtures and synergistic mixtures thereof.The fungicidal compounds of the present disclosure are often applied inconjunction with one or more other fungicides to control a wider varietyof undesirable diseases. When used in conjunction with otherfungicide(s), the presently claimed compounds may be formulated with theother fungicide(s), tank-mixed with the other fungicide(s) or appliedsequentially with the other fungicide(s). Such other fungicides mayinclude 2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol,8-hydroxyquinoline sulfate, ametoctradin, amisulbrom, antimycin,Ampelomyces quisqualis, azaconazole, azoxystrobin, Bacillus subtilis,Bacillus subtilis strain QST713, benalaxyl, benomyl,benthiavalicarb-isopropyl, benzovindiflupyr,benzylaminobenzene-sulfonate (BABS) salt, bicarbonates, biphenyl,bismerthiazol, bitertanol, bixafen, blasticidin-S, borax, Bordeauxmixture, boscalid, bromuconazole, bupirimate, calcium polysulfide,captafol, captan, carbendazim, carboxin, carpropamid, carvone,chlazafenone, chloroneb, chlorothalonil, chlozolinate, Coniothyriumminitans, copper hydroxide, copper octanoate, copper oxychloride, coppersulfate, copper sulfate (tribasic), coumoxystrobin, cuprous oxide,cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, dazomet,debacarb, diammonium ethylenebis-(dithiocarbamate), dichlofluanid,dichlorophen, diclocymet, diclomezine, dichloran, diethofencarb,difenoconazole, difenzoquat ion, diflumetorim, dimethomorph,dimoxystrobin, diniconazole, diniconazole-M, dinobuton, dinocap,diphenylamine, dipymetitrone, dithianon, dodemorph, dodemorph acetate,dodine, dodine free base, edifenphos, enestrobin, enestroburin,enoxastrobin, epoxiconazole, ethaboxam, ethoxyquin, etridiazole,famoxadone, fenamidone, fenaminostrobin, fenarimol, fenbuconazole,fenfuram, fenhexamid, fenoxanil, fenpiclonil, fenpropidin,fenpropimorph, fenpyrazamine, fentin, fentin acetate, fentin hydroxide,ferbam, ferimzone, fluazinam, fludioxonil, flufenoxystrobin, flumorph,fluopicolide, fluopyram, fluoroimide, fluoxastrobin, fluquinconazole,flusilazole, flusulfamide, flutianil, flutolanil, flutriafol,fluxapyroxad, folpet, formaldehyde, fosetyl, fosetyl-aluminium,fuberidazole, furalaxyl, furametpyr, guazatine, guazatine acetates,GY-81, hexachlorobenzene, hexaconazole, hymexazol, imazalil, imazalilsulfate, imibenconazole, iminoctadine, iminoctadine triacetate,iminoctadine tris(albesilate), iodocarb, ipconazole, ipfenpyrazolone,iprobenfos, iprodione, iprovalicarb, isofetamid, isoprothiolane,isopyrazam, isotianil, kasugamycin, kasugamycin hydrochloride hydrate,kresoxim-methyl, laminarin, mancopper, mancozeb, mandestrobin,mandipropamid, maneb, mefenoxam, mepanipyrim, mepronil, meptyl-dinocap,mercuric chloride, mercuric oxide, mercurous chloride, metalaxyl,metalaxyl-M, metam, metam-ammonium, metam-potassium, metam-sodium,metconazole, methasulfocarb, methyl iodide, methyl isothiocyanate,metiram, metominostrobin, metrafenone, mildiomycin, myclobutanil, nabam,nitrothal-isopropyl, nuarimol, octhilinone, ofurace, oleic acid (fattyacids), orysastrobin, oxadixyl, oxathiapiprolin, oxine-copper,oxpoconazole fumarate, oxycarboxin, pefurazoate, penconazole,pencycuron, penflufen, pentachlorophenol, pentachlorophenyl laurate,penthiopyrad, phenylmercury acetate, phosphonic acid, phthalide,picarbutrazox, picoxystrobin, polyoxin B, polyoxins, polyoxorim,potassium bicarbonate, potassium hydroxyquinoline sulfate, probenazole,prochloraz, procymidone, propamocarb, propamocarb hydrochloride,propiconazole, propineb, proquinazid, prothioconazole, pyraclostrobin,pyrametostrobin, pyraoxystrobin, pyraziflumid, pyrazophos, pyribencarb,pyributicarb, pyrifenox, pyrimethanil, pyriofenone, pyrisoxazole,pyroquilon, quinoclamine, quinoxyfen, quintozene, Reynoutriasachalinensis extract, sedaxane, silthiofam, simeconazole, sodium2-phenylphenoxide, sodium bicarbonate, sodium pentachlorophenoxide,spiroxamine, sulfur, SYP-Z048, tar oils, tebuconazole, tebufloquin,tecnazene, tetraconazole, thiabendazole, thifluzamide,thiophanate-methyl, thiram, tiadinil, tolclofos-methyl, tolprocarb,tolylfluanid, triadimefon, triadimenol, triazoxide, triclopyricarb,tricyclazole, tridemorph, trifloxystrobin, triflumizole, triforine,triticonazole, validamycin, valifenalate, valiphenal, vinclozolin,zineb, ziram, zoxamide, Candida oleophila, Fusarium oxysporum,Gliocladium spp., Phlebiopsis gigantea, Streptomyces griseoviridis,Trichoderma spp.,(RS)—N-(3,5-dichlorophenyl)-2-(methoxymethyl)-succinimide,1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone hydrate,1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane,2-(2-heptadecyl-2-imidazolin-1-yl)ethanol,2,3-dihydro-5-phenyl-1,4-dithi-ine 1,1,4,4-tetraoxide,2-methoxyethylmercury acetate, 2-methoxyethylmercury chloride,2-methoxyethylmercury silicate, 3-(4-chlorophenyl)-5-methylrhodanine,4-(2-nitroprop-1-enyl)phenyl thiocyanateme, ampropylfos, anilazine,azithiram, barium polysulfide, Bayer 32394, benodanil, benquinox,bentaluron, benzamacril, benzamacril-isobutyl, benzamorf, binapacryl,bis(methylmercury) sulfate, bis(tributyltin) oxide, buthiobate, cadmiumcalcium copper zinc chromate sulfate, carbamorph, CECA, chlobenthiazone,chloraniformethan, chlorfenazole, chlorquinox, climbazole, copperbis(3-phenylsalicylate), copper zinc chromate, cufraneb, cuprichydrazinium sulfate, cuprobam, cyclafuramid, cypendazole, cyprofuram,decafentin, dichlone, dichlozoline, diclobutrazol, dimethirimol,dinocton, dinosulfon, dinoterbon, dipyrithione, ditalimfos, dodicin,drazoxolon, EBP, ESBP, etaconazole, etem, ethirim, fenaminosulf,fenapanil, fenitropan, fluotrimazole, furcarbanil, furconazole,furconazole-cis, furmecyclox, furophanate, glyodine, griseofulvin,halacrinate, Hercules 3944, hexylthiofos, ICIA0858, isopamphos,isovaledione, mebenil, mecarbinzid, metazoxolon, methfuroxam,methylmercury dicyandiamide, metsulfovax, milneb, mucochloric anhydride,myclozolin, N-3,5-dichlorophenyl-succinimide,N-3-nitrophenylitaconimide, natamycin,N-ethylmercurio-4-toluenesulfonanilide, nickelbis(dimethyldithiocarbamate), OCH, phenylmercurydimethyldithiocarbamate, phenylmercury nitrate, phosdiphen, prothiocarb,prothiocarb hydrochloride, pyracarbolid, pyridinitril, pyroxychlor,pyroxyfur, quinacetol, quinacetol sulfate, quinazamid, quinconazole,rabenzazole, salicylanilide, SSF-109, sultropen, tecoram, thiadifluor,thicyofen, thiochlorfenphim, thiophanate, thioquinox, tioxymid,triamiphos, triarimol, triazbutil, trichlamide, urbacid, zarilamid, andany combinations thereof.

Additionally, the compounds described herein may be combined with otherpesticides, including insecticides, nematocides, miticides,arthropodicides, bactericides or combinations thereof that arecompatible with the compounds of the present disclosure in the mediumselected for application, and not antagonistic to the activity of thepresent compounds to form pesticidal mixtures and synergistic mixturesthereof. The fungicidal compounds of the present disclosure may beapplied in conjunction with one or more other pesticides to control awider variety of undesirable pests. When used in conjunction with otherpesticides, the presently claimed compounds may be formulated with theother pesticide(s), tank-mixed with the other pesticide(s) or appliedsequentially with the other pesticide(s). Typical insecticides include,but are not limited to: 1,2-dichloropropane, abamectin, acephate,acetamiprid, acethion, acetoprole, acrinathrin, acrylonitrile,afidopyropen, alanycarb, aldicarb, aldoxycarb, aldrin, allethrin,allosamidin, allyxycarb, alpha-cypermethrin, alpha-ecdysone,alpha-endosulfan, amidithion, aminocarb, amiton, amiton oxalate,amitraz, anabasine, athidathion, azadirachtin, azamethiphos,azinphos-ethyl, azinphos-methyl, azothoate, barium hexafluorosilicate,barthrin, bendiocarb, benfuracarb, bensultap, beta-cyfluthrin,beta-cypermethrin, bifenthrin, bioallethrin, bioethanomethrin,biopermethrin, bistrifluron, borax, boric acid, broflanilide,bromfenvinfos, bromocyclen, bromo-DDT, bromophos, bromophos-ethyl,bufencarb, buprofezin, butacarb, butathiofos, butocarboxim, butonate,butoxycarboxim, cadusafos, calcium arsenate, calcium polysulfide,camphechlor, carbanolate, carbaryl, carbofuran, carbon disulfide, carbontetrachloride, carbophenothion, carbosulfan, cartap, cartaphydrochloride, chlorantraniliprole, chlorbicyclen, chlordane,chlordecone, chlordimeform, chlordimeform hydrochloride, chlorethoxyfos,chlorfenapyr, chlorfenvinphos, chlorfluazuron, chlormephos, chloroform,chloropicrin, chlorphoxim, chlorprazophos, chlorpyrifos,chlorpyrifos-methyl, chlorthiophos, chromafenozide, cinerin I, cinerinII, cinerins, cismethrin, clacyfos, cloethocarb, closantel,clothianidin, copper acetoarsenite, copper arsenate, copper naphthenate,copper oleate, coumaphos, coumithoate, crotamiton, crotoxyphos,crufomate, cryolite, cyanofenphos, cyanophos, cyanthoate,cyantraniliprole, cyclaniliprole, cyclethrin, cycloprothrin, cyfluthrin,cyhalothrin, cypermethrin, cyphenothrin, cyromazine, cythioate, DDT,decarbofuran, deltamethrin, demephion, demephion-O, demephion-S,demeton, demeton-methyl, demeton-O, demeton-O-methyl, demeton-S,demeton-S-methyl, demeton-S-methylsulphon, diafenthiuron, dialifos,diatomaceous earth, diazinon, dicapthon, dichlofenthion, dichlorvos,dicloromezotiaz, dicresyl, dicrotophos, dicyclanil, dieldrin,diflubenzuron, dilor, dimefluthrin, dimefox, dimetan, dimethoate,dimethrin, dimethylvinphos, dimetilan, dinex, dinex-diclexine, dinoprop,dinosam, dinotefuran, diofenolan, dioxabenzofos, dioxacarb, dioxathion,disulfoton, dithicrofos, d-limonene, DNOC, DNOC-ammonium,DNOC-potassium, DNOC-sodium, doramectin, ecdysterone, emamectin,emamectin benzoate, EMPC, empenthrin, endosulfan, endothion, endrin,EPN, epofenonane, eprinomectin, esdepallethrine, esfenvalerate, etaphos,ethiofencarb, ethion, ethiprole, ethoate-methyl, ethoprophos, ethylformate, ethyl-DDD, ethylene dibromide, ethylene dichloride, ethyleneoxide, etofenprox, etrimfos, EXD, famphur, fenamiphos, fenazaflor,fenchlorphos, fenethacarb, fenfluthrin, fenitrothion, fenobucarb,fenoxacrim, fenoxycarb, fenpirithrin, fenpropathrin, fensulfothion,fenthion, fenthion-ethyl, fenvalerate, fipronil, flometoquin,flonicamid, flubendiamide, flucofuron, flucycloxuron, flucythrinate,flufenerim, flufenoxuron, flufenprox, flufiprole, fluhexafon,flupyradifurone, fluvalinate, fonofos, formetanate, formetanatehydrochloride, formothion, formparanate, formparanate hydrochloride,fosmethilan, fospirate, fosthietan, furathiocarb, furethrin,gamma-cyhalothrin, gamma-HCH, halfenprox, halofenozide, HCH, HEOD,heptachlor, heptafluthrin, heptenophos, heterophos, hexaflumuron, HHDN,hydramethylnon, hydrogen cyanide, hydroprene, hyquincarb, imidacloprid,imiprothrin, indoxacarb, iodomethane, IPSP, isazofos, isobenzan,isocarbophos, isodrin, isofenphos, isofenphos-methyl, isoprocarb,isoprothiolane, isothioate, isoxathion, ivermectin, jasmolin I, jasmolinII, jodfenphos, juvenile hormone I, juvenile hormone II, juvenilehormone III, kappa-bifenthrin, kappa-tefluthrin, kelevan, kinoprene,lambda-cyhalothrin, lead arsenate, lepimectin, leptophos, lindane,lirimfos, lufenuron, lythidathion, malathion, malonoben, mazidox,mecarbam, mecarphon, menazon, mephosfolan, mercurous chloride,mesulfenfos, metaflumizone, methacrifos, methamidophos, methidathion,methiocarb, methocrotophos, methomyl, methoprene, methoxychlor,methoxyfenozide, methyl bromide, methyl isothiocyanate,methylchloroform, methylene chloride, metofluthrin, metolcarb,metoxadiazone, mevinphos, mexacarbate, milbemectin, milbemycin oxime,mipafox, mirex, molosultap, momfluorothrin, monocrotophos, monomehypo,monosultap, morphothion, moxidectin, naftalofos, naled, naphthalene,nicotine, nifluridide, nitenpyram, nithiazine, nitrilacarb, novaluron,noviflumuron, omethoate, oxamyl, oxydemeton-methyl, oxydeprofos,oxydisulfoton, para-dichlorobenzene, parathion, parathion-methyl,penfluron, pentachlorophenol, permethrin, phenkapton, phenothrin,phenthoate, phorate, phosalone, phosfolan, phosmet, phosnichlor,phosphamidon, phosphine, phoxim, phoxim-methyl, pirimetaphos,pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, potassium arsenite,potassium thiocyanate, pp′-DDT, prallethrin, precocene I, precocene II,precocene II, primidophos, profenofos, profluralin, promacyl, promecarb,propaphos, propetamphos, propoxur, prothidathion, prothiofos, prothoate,protrifenbute, pyflubumide, pyraclofos, pyrafluprole, pyrazophos,pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyridaben,pyridalyl, pyridaphenthion, pyrifluquinazon, pyrimidifen,pyriminostrobin, pyrimitate, pyriprole, pyriproxyfen, quassia,quinalphos, quinalphos-methyl, quinothion, rafoxanide, resmethrin,rotenone, ryania, sabadilla, schradan, selamectin, silafluofen, silicagel, sodium arsenite, sodium fluoride, sodium hexafluorosilicate, sodiumthiocyanate, sophamide, spinetoram, spinosad, spiromesifen,spirotetramat, sulcofuron, sulcofuron-sodium, sulfluramid, sulfotep,sulfoxaflor, sulfuryl fluoride, sulprofos, tau-fluvalinate, tazimcarb,TDE, tebufenozide, tebufenpyrad, tebupirimfos, teflubenzuron,tefluthrin, temephos, TEPP, terallethrin, terbufos, tetrachloroethane,tetrachlorvinphos, tetramethrin, tetramethylfluthrin, tetraniliprole,theta-cypermethrin, thiacloprid, thiamethoxam, thicrofos, thiocarboxime,thiocyclam, thiocyclam oxalate, thiodicarb, thiofanox, thiometon,thiosultap, thiosultap-disodium, thiosultap-monosodium, thuringiensin,tioxazafen, tolfenpyrad, tralomethrin, transfluthrin, transpermethrin,triarathene, triazamate, triazophos, trichlorfon, trichlormetaphos-3,trichloronat, trifenofos, triflumezopyrim, triflumuron, trimethacarb,triprene, vamidothion, vaniliprole, XMC, xylylcarb, zeta-cypermethrin,zolaprofos, and any combinations thereof.

Additionally, the compounds described herein may be combined withherbicides that are compatible with the compounds of the presentdisclosure in the medium selected for application, and not antagonisticto the activity of the present compounds to form pesticidal mixtures andsynergistic mixtures thereof. The fungicidal compounds of the presentdisclosure may be applied in conjunction with one or more herbicides tocontrol a wide variety of undesirable plants. When used in conjunctionwith herbicides, the presently claimed compounds may be formulated withthe herbicide(s), tank-mixed with the herbicide(s) or appliedsequentially with the herbicide(s). Typical herbicides include, but arenot limited to: 4-CPA; 4-CPB; 4-CPP; 2,4-D; 3,4-DA; 2,4-DB; 3,4-DB;2,4-DEB; 2,4-DEP; 3,4-DP; 2,3,6-TBA; 2,4,5-T; 2,4,5-TB; acetochlor,acifluorfen, aclonifen, acrolein, alachlor, allidochlor, alloxydim,allyl alcohol, alorac, ametridione, ametryn, amibuzin, amicarbazone,amidosulfuron, aminocyclopyrachlor, aminopyralid, amiprofos-methyl,amitrole, ammonium sulfamate, anilofos, anisuron, asulam, atraton,atrazine, azafenidin, azimsulfuron, aziprotryne, barban, BCPC,beflubutamid, benazolin, bencarbazone, benfluralin, benfuresate,bensulfuron, bensulide, bentazone, benzadox, benzfendizone, benzipram,benzobicyclon, benzofenap, benzofluor, benzoylprop, benzthiazuron,bicyclopyrone, bifenox, bilanafos, bispyribac, borax, bromacil,bromobonil, bromobutide, bromofenoxim, bromoxynil, brompyrazon,butachlor, butafenacil, butamifos, butenachlor, buthidazole, buthiuron,butralin, butroxydim, buturon, butylate, cacodylic acid, cafenstrole,calcium chlorate, calcium cyanamide, cambendichlor, carbasulam,carbetamide, carboxazole, chlorprocarb, carfentrazone, CDEA, CEPC,chlomethoxyfen, chloramben, chloranocryl, chlorazifop, chlorazine,chlorbromuron, chlorbufam, chloreturon, chlorfenac, chlorfenprop,chlorflurazole, chlorflurenol, chloridazon, chlorimuron, chlornitrofen,chloropon, chlorotoluron, chloroxuron, chloroxynil, chlorpropham,chlorsulfuron, chlorthal, chlorthiamid, cinidon-ethyl, cinmethylin,cinosulfuron, cisanilide, clethodim, cliodinate, clodinafop, clofop,clomazone, clomeprop, cloprop, cloproxydim, clopyralid, cloransulam,CMA, copper sulfate, CPMF, CPPC, credazine, cresol, cumyluron,cyanatryn, cyanazine, cycloate, cyclopyrimorate, cyclosulfamuron,cycloxydim, cycluron, cyhalofop, cyperquat, cyprazine, cyprazole,cypromid, daimuron, dalapon, dazomet, delachlor, desmedipham, desmetryn,di-allate, dicamba, dichlobenil, dichloralurea, dichlormate,dichlorprop, dichlorprop-P, diclofop, diclosulam, diethamquat,diethatyl, difenopenten, difenoxuron, difenzoquat, diflufenican,diflufenzopyr, dimefuron, dimepiperate, dimethachlor, dimethametryn,dimethenamid, dimethenamid-P, dimexano, dimidazon, dinitramine,dinofenate, dinoprop, dinosam, dinoseb, dinoterb, diphenamid,dipropetryn, diquat, disul, dithiopyr, diuron, DMPA, DNOC, DSMA, EBEP,eglinazine, endothal, epronaz, EPTC, erbon, esprocarb, ethalfluralin,ethametsulfuron, ethidimuron, ethiolate, ethofumesate, ethoxyfen,ethoxysulfuron, etinofen, etnipromid, etobenzanid, EXD, fenasulam,fenoprop, fenoxaprop, fenoxaprop-P, fenoxasulfone, fenquinotrione,fenteracol, fenthiaprop, fentrazamide, fenuron, ferrous sulfate,flamprop, flamprop-M, flazasulfuron, florasulam, fluazifop, fluazifop-P,fluazolate, flucarbazone, flucetosulfuron, fluchloralin, flufenacet,flufenican, flufenpyr, flumetsulam, flumezin, flumiclorac, flumioxazin,flumipropyn, fluometuron, fluorodifen, fluoroglycofen, fluoromidine,fluoronitrofen, fluothiuron, flupoxam, flupropacil, flupropanate,flupyrsulfuron, fluridone, flurochloridone, fluroxypyr, flurtamone,fluthiacet, fomesafen, foramsulfuron, fosamine, furyloxyfen,glufosinate, glufosinate-P, glyphosate, halauxifen, halosafen,halosulfuron, haloxydine, haloxyfop, haloxyfop-P, hexachloroacetone,hexaflurate, hexazinone, imazamethabenz, imazamox, imazapic, imazapyr,imazaquin, imazethapyr, imazosulfuron, indanofan, indaziflam, iodobonil,iodomethane, iodosulfuron, iofensulfuron, ioxynil, ipazine,ipfencarbazone, iprymidam, isocarbamid, isocil, isomethiozin,isonoruron, isopolinate, isopropalin, isoproturon, isouron, isoxaben,isoxachlortole, isoxaflutole, isoxapyrifop, karbutilate, ketospiradox,lactofen, lenacil, linuron, MAA, MAMA, MCPA, MCPA-thioethyl, MCPB,mecoprop, mecoprop-P, medinoterb, mefenacet, mefluidide, mesoprazine,mesosulfuron, mesotrione, metam, metamifop, metamitron, metazachlor,metazosulfuron, metflurazon, methabenzthiazuron, methalpropalin,methazole, methiobencarb, methiozolin, methiuron, methometon,methoprotryne, methyl bromide, methyl isothiocyanate, methyldymron,metobenzuron, metobromuron, metolachlor, metosulam, metoxuron,metribuzin, metsulfuron, molinate, monalide, monisouron,monochloroacetic acid, monolinuron, monuron, morfamquat, MSMA,naproanilide, napropamide, napropamide-M, naptalam, neburon,nicosulfuron, nipyraclofen, nitralin, nitrofen, nitrofluorfen,norflurazon, noruron, OCH, orbencarb, ortho-dichlorobenzene,orthosulfamuron, oryzalin, oxadiargyl, oxadiazon, oxapyrazon,oxasulfuron, oxaziclomefone, oxyfluorfen, parafluron, paraquat,pebulate, pelargonic acid, pendimethalin, penoxsulam, pentachlorophenol,pentanochlor, pentoxazone, perfluidone, pethoxamid, phenisopham,phenmedipham, phenmedipham-ethyl, phenobenzuron, phenylmercury acetate,picloram, picolinafen, pinoxaden, piperophos, potassium arsenite,potassium azide, potassium cyanate, pretilachlor, primisulfuron,procyazine, prodiamine, profluazol, profluralin, profoxydim,proglinazine, prometon, prometryn, propachlor, propanil, propaquizafop,propazine, propham, propisochlor, propoxycarbazone, propyrisulfuron,propyzamide, prosulfalin, prosulfocarb, prosulfuron, proxan, prynachlor,pydanon, pyraclonil, pyraflufen, pyrasulfotole, pyrazolynate,pyrazosulfuron, pyrazoxyfen, pyribenzoxim, pyributicarb, pyriclor,pyridafol, pyridate, pyriftalid, pyriminobac, pyrimisulfan, pyrithiobac,pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quinoclamine,quinonamid, quizalofop, quizalofop-P, rhodethanil, rimsulfuron,saflufenacil, S-metolachlor, sebuthylazine, secbumeton, sethoxydim,siduron, simazine, simeton, simetryn, SMA, sodium arsenite, sodiumazide, sodium chlorate, sulcotrione, sulfallate, sulfentrazone,sulfometuron, sulfosulfuron, sulfuric acid, sulglycapin, swep, TCA,tebutam, tebuthiuron, tefuryltrione, tembotrione, tepraloxydim,terbacil, terbucarb, terbuchlor, terbumeton, terbuthylazine, terbutryn,tetrafluron, thenylchlor, thiazafluron, thiazopyr, thidiazimin,thidiazuron, thiencarbazone-methyl, thifensulfuron, thiobencarb,tiafenacil, tiocarbazil, tioclorim, tolpyralate, topramezone,tralkoxydim, triafamone, tri-allate, triasulfuron, triaziflam,tribenuron, tricamba, triclopyr, tridiphane, trietazine,trifloxysulfuron, trifludimoxazin, trifluralin, triflusulfuron, trifop,trifopsime, trihydroxytriazine, trimeturon, tripropindan, tritac,tritosulfuron, vernolate, and xylachlor.

Another embodiment of the present disclosure is a method for the controlor prevention of fungal attack. This method comprises applying to thesoil, plant, roots, foliage, or locus of the fungus, or to a locus inwhich the infestation is to be prevented (for example applying to cerealor grape plants), a fungicidally effective amount of one or more of thecompounds of Formula I. The compounds are suitable for treatment ofvarious plants at fungicidal levels, while exhibiting low phytotoxicity.The compounds may be useful both in a protectant and/or an eradicantfashion.

The compounds have been found to have significant fungicidal effectparticularly for agricultural use. Many of the compounds areparticularly effective for use with agricultural crops and horticulturalplants.

It will be understood by those skilled in the art that the efficacy ofthe compound for the foregoing fungi establishes the general utility ofthe compounds as fungicides.

The compounds have broad ranges of activity against fungal pathogens.Exemplary pathogens may include, but are not limited to, causing agentof wheat leaf blotch (Zymoseptoria tritici), wheat brown rust (Pucciniatriticina), wheat stripe rust (Puccinia striiformis), scab of apple(Venturia inaequalis), powdery mildew of grapevine (Uncinula necator),barley scald (Rhynchosporium secalis), blast of rice (Pyriculariaoryzae), rust of soybean (Phakopsora pachyrhizi), glume blotch of wheat(Leptosphaeria nodorum), powdery mildew of wheat (Blumeria graminis f.sp. tritici), powdery mildew of barley (Blumeria graminis f. sp.hordei), powdery mildew of cucurbits (Erysiphe cichoracearum),anthracnose of cucurbits (Colletotrichum lagenarium), leaf spot of beet(Cercospora beticola), early blight of tomato (Alternaria solani), andspot blotch of barley (Cochliobolus sativus). The exact amount of theactive material to be applied is dependent not only on the specificactive material being applied, but also on the particular actiondesired, the fungal species to be controlled, and the stage of growththereof, as well as the part of the plant or other product to becontacted with the compound. Thus, all the compounds, and formulationscontaining the same, may not be equally effective at similarconcentrations or against the same fungal species.

The compounds are effective in use with plants in a disease-inhibitingand phytologically acceptable amount. The term “disease-inhibiting andphytologically acceptable amount” refers to an amount of a compound thatkills or inhibits the plant disease for which control is desired, but isnot significantly toxic to the plant. This amount will generally be fromabout 0.1 to about 1000 ppm (parts per million), with 1 to 500 ppm beingpreferred. The exact concentration of compound required varies with thefungal disease to be controlled, the type of formulation employed, themethod of application, the particular plant species, climate conditions,and the like. A suitable application rate is typically in the range fromabout 0.10 to about 4 pounds/acre (about 0.01 to 0.45 grams per squaremeter, g/m²).

Any range or desired value given herein may be extended or alteredwithout losing the effects sought, as is apparent to the skilled personfor an understanding of the teachings herein.

The compounds of Formula I may be made using well-known chemicalprocedures. Intermediates not specifically mentioned in this disclosureare either commercially available, may be made by routes disclosed inthe chemical literature, or may be readily synthesized from commercialstarting materials utilizing standard procedures.

General Schemes

The following schemes illustrate approaches to generating picolinamidecompounds of Formula I. The following descriptions and examples areprovided for illustrative purposes and should not be construed aslimiting in terms of substituents or substitution patterns.

Compounds of Formula 1.1, wherein R₃ and R₁₂ are as originally definedand are equivalent, can be prepared by the methods shown in Scheme 1,step a. The compound of Formula 1.0 can be treated with anorganometallic nucleophile such as phenylmagnesium bromide (PhMgBr) in apolar aprotic solvent such as tetrahydrofuran (THF) at a temperature ofabout 0° C. to 23° C. to afford compounds of Formula 1.1, wherein R₃ andR₁₂ are as previously defined, as shown in a.

Compounds of Formula 2.2, wherein R₃ is as originally defined and may ormay not be equal to R₁₂, can be prepared by the methods shown in Scheme2, steps a-c. Compounds of Formula 2.2, wherein R₃ and R₁₂ are aspreviously defined but not an electron-deficient aryl or heteroarylgroup and may or may not be equivalent, can be obtained by treating thecompounds of Formula 2.0, wherein R₃ and R₁₂ are as previously definedbut not an electron-deficient aryl or heteroaryl group and may or maynot be equivalent, with a mixture of a hydride reagent, such astriethylsilane (Et₃SiH), and an acid, such as 2,2,2-trifluoroacetic acid(TFA) in a halogenated solvent such as dichloromethane (DCM) at atemperature of about 0° C. to 23° C., as depicted in a. Alternatively,compounds of Formula 2.1, wherein R₃ and R₁₂ are an electron-deficientaryl or heteroaryl group and may or may not be equivalent, can beobtained by treating the compounds of Formula 2.0, wherein R₃ and R₁₂are an electron-deficient aryl or heteroaryl group and may or may not beequivalent, with a base, such as sodium hydride (NaH), and a catalyst,such as imidazole, in a polar aprotic solvent such as THF at atemperature of about 23° C., followed by sequential addition of carbondisulfide (CS₂) and an alkyl iodide, such as iodomethane (MeI), asdepicted in b. Compounds of Formula 2.2, wherein R₃ and R₁₂ are anelectron-deficient aryl or heteroaryl group and may or may not beequivalent, can be obtained by treating the compounds of Formula 2.1,wherein R₃ and R₁₂ are as previously defined and may or may not beequivalent, with a tin reagent, such as tributyltin hydride, and aradical initiator, such as azobisisobutyronitrile (AIBN), in a nonpolarsolvent such as toluene at a temperature of about 115° C., as depictedin c.

Compounds of Formula 3.1, wherein R₃ and R₁₂ are as originally definedand may or may not be equivalent, can be prepared according to themethod outlined in Scheme 3, step a. Compounds of Formula 3.1, whereinR₃ and R₁₂ are as originally defined and may or may not be equivalent,can be prepared from compounds of Formula 3.0, wherein R₃ and R₁₂ are aspreviously defined and may or may not be equivalent, by treating with abase, such as NaH and an alkyl halide, such as MeI, in a polar aproticsolvent like N,N-dimethylformamide (DMF) at a temperature of about 0° C.to 23° C., as depicted in a.

Compounds of Formula 4.1, wherein R₃ and R₁₂ are as originally definedand may or may not be equivalent, can be prepared according to themethod outlined in Scheme 4, step a. Compounds of Formula 4.1, whereinR₃ and R₁₂ are as originally defined and may or may not be equivalent,can be prepared from compounds of Formula 4.0, wherein R₃ and R₁₂ are aspreviously defined and may or may not be equivalent, by treating with afluorination reagent, such as (diethylamino)sulfur trifluoride (DAST),in a halogenated solvent such as DCM at a temperature of about 0° C. to23° C., as depicted in a.

Compounds of Formula 5.3, wherein R₃, R₄, and R₁₂ are as originallydefined and R₃ may or may not be equivalent to R₁₂, can be preparedaccording to the methods outlined in Scheme 5, steps a-c. Compounds ofFormula 5.3, wherein R₃, R₄, and R₁₂ are as originally defined and R₃may or may not be equivalent to R₁₂, can be prepared from compounds ofFormula 5.0, wherein R₃, R₄, and R₁₂ are as originally defined and R₃may or may not be equivalent to R₁₂, by treating with a catalyst such aspalladium on carbon (Pd/C) in a mixture of an unsaturated hydrocarbonsolvent, such as cyclohexene, and a polar protic solvent, such asethanol (EtOH), at an elevated temperature of about 65° C., as shown ina. Alternatively, compounds of Formula 5.3, wherein R₃ and R₁₂ are anelectron-deficient aryl or heteroaryl group and may or may not beequivalent and R₄ is hydroxyl (OH) or alkoxy, can be obtained bytreating compounds of Formula 5.1, wherein R₃, R₄, and R₁₂ are aspreviously defined and R₃ may or may not be equivalent to R₁₂, with amixture of a hydride reagent, such as Et₃SiH, and an acid, such as TFAin a halogenated solvent such as DCM at a temperature of about 0° C. to23° C., as indicated in b. Additionally, compounds of Formula 5.3,wherein R₃ and R₁₂ are as originally defined but not anelectron-deficient aryl or heteroaryl group and may or may not beequivalent, and R₄ is a proton (H), can be obtained by treating thecompounds of Formula 5.2, wherein R₃, R₄, and R₁₂ are as previouslydefined and R₃ may or may not be equivalent to R₁₂, with a mixture of ahydride reagent, such as Et₃SiH, and an acid, such as TFA in ahalogenated solvent such as DCM at a temperature of about 0° C. to 23°C., as depicted in c.

Compounds of Formula 6.2, wherein R₃ and R₁₂ are an electron-deficientaryl or heteroaryl group and equivalent, can be prepared according tothe methods outlined in Scheme 6, steps a-b. Compounds of Formula 6.1,wherein R₃ and R₁₂ are as described previously, can be prepared fromcompound of Formula 6.0, by treating with an aryl bromide, such as4-bromobenzonitrile, in the presence of a Pd catalyst, such as XPhos PdG3 (GAS #1445085-55-1, commercially available from Sigma-Aldrich), in apolar aprotic solvent such as THF at a temperature of about 55° C., asindicated in a. Compounds of Formula 6.2, wherein R₃ and R₁₂ are asdescribed previously, can be prepared from compound of Formula 6.1,wherein R₃ and R₁₂ are as described previously, by treating with ahydride reagent, such as borane dimethyl sulfide complex, in thepresence of a catalyst, such as (R)-(+)-2-Methyl-CBS-oxazaborolidine, ina polar protic solvent, such as methanol (MeOH), at a temperature ofabout 0′° C., as indicated in b.

Compounds of Formula 7.2, wherein R₃ and R₁₂ are as originally definedand equivalent, can be prepared according to the methods outlined inScheme 7, steps a-b. Compounds of Formula 7.1, wherein R₃ and R₁₂ are asdescribed previously, can be prepared from compounds of Formula 7.0, bytreating with a catalyst, such as SbCl₅, in a halogenated solvent suchas DCM at a temperature of about 23° C., as indicated in a. Compounds ofFormula 7.2, wherein R₃ and R₁₂ are as described previously, can beprepared from compound of Formula 7.1, wherein R₃ and R₁₂ are asdescribed previously, by treating with a hydride reagent, such as boranedimethyl sulfide complex, in the presence of a catalyst, such as(R)-(+)-2-Methyl-CBS-oxazaborolidine, in a polar protic solvent, such asmethanol (MeOH), at a temperature of about 23° C., as indicated in b.

Compounds of Formula 8.1, wherein n is either 0 or 1, and W is eitherCH₂ or O, can be prepared according to the method outlined in Scheme 8,step a. Compounds of Formula 8.1, wherein n is either 0 or 1, and W iseither CH₂ or O, can be prepared from compounds of Formula 8.0, whereinn is either 0 or 1, and W is either CH₂ or O, by treating with a base,such as n-butyllithium (n-BuLi), and an aldehyde, such as acetaldehyde,in a polar aprotic solvent such as THF at a temperature of about −78° C.to 23° C., as indicated in a.

Compounds of Formula 9.1, wherein R₃ and R₁₂ are as originally defined,can be prepared according to the method outlined in Scheme 9, step a.Compounds of Formula 9.1, wherein R₃ and R₁₂ are as originally defined,can be prepared from compounds of Formula 9.0, wherein R₃ is asoriginally defined (Formula 9.0 is either commerically available, orcould be prepared from asymmetric Shi epoxidation of the correspondingE-olefin precursor, as reported in Wang, Z.-X.; Tu, Y.; Frohn, M.;Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224), by treatingwith a pre-mixed suspension of a copper(I) salt, such as copper iodide(CuI), and an organometallic nucleophile, such as4-(trifluoromethyl)phenylmagnesium bromide in a polar aprotic solventsuch as THF, at a temperature of about −78° C. to 23° C., as shown in a.

Compounds of Formula 10.2, wherein R₁, R₂, R₃, R₄ and R₁₂ are asoriginally defined, can be prepared according to the method outlined inScheme 10, step a. Compounds of Formula 10.0, wherein R₁ is asoriginally defined, can be treated with alcohols of Formula 10.1,wherein R₂, R₃, R₄ and R₁₂ are as originally defined, and a couplingreagent such as 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-aminehydrochloride (EDC), and a catalyst such as N,N-dimethylpyridin-4-amine(DMAP) in a halogenated solvent like DCM to afford compounds of Formula10.2, wherein R₁, R₂, R₃, R₄ and R₁₂ are as previously defined, as shownin a.

Compounds of Formula 11.2, wherein R₁, R₂, R₃, R₄, R₆, R₁₂ and Z are asoriginally defined, can be prepared according to the methods outlined inScheme 11, steps a-b. As depicted in a, compounds of Formula 11.2,wherein R₁, R₂, R₃, R₄ and R₁₂ are as originally defined, can besubjected to an acid, such as a 4 normal (N) solution of hydrogenchloride (HCl) in dioxane, in a halogenated solvent such as DCM toafford compounds of Formula 9.0, wherein R₁, R₂, R₃, R₄ and R₁₂ are asoriginally defined, as shown in a.

Compounds of Formula 11.0, wherein R₁, R₂, R₃, R₄ and R₁₂ are asoriginally defined, can be treated with compounds of Formula 11.1,wherein R₆ and Z are as originally defined, in the presence of a base,such as diisopropylethylamine (DIPEA), and a peptide coupling reagent,such as benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate (PyBOP), in an halogenated solvent like DCM, toafford compounds of Formula 11.2, wherein R₁, R₂, R₃, R₄, R₆, R₁₂ and Zare as originally defined, as shown in b.

Compounds of Formula 12.0, wherein R₁, R₂, R₃, R₄, R₆, R₇, R₁₂ and Z areas originally defined, can be prepared according to the method outlinedin Scheme 12, step a. As shown in a, compounds of Formula 11.2, whereinR₁, R₂, R₃, R₄, R₆, R₁₂ and Z are as originally defined, can be treatedwith an appropriate alkyl halide with or without a reagent such assodium iodide (NaI) and an alkali carbonate base, such as sodiumcarbonate (Na₂CO₃) or potassium carbonate (K₂CO₃), in a solvent likeacetone at a temperature of about 55° C., or by treatment with an acylhalide in the presence of an amine base, such as pyridine, triethylamine(Et₃N), DMAP, or mixtures thereof, in an aprotic solvent such as DCM, ata temperature of about 23° C., to afford compounds of Formula 12.0wherein R₁, R₂, R₃, R₄, R₆, R₇, R₁₂ and Z are as originally defined.

EXAMPLES

The chemistry in the following examples may be conducted using eitherenantiomer of 2-((tert-butoxycarbonyl)amino)propanoic acid (Boc-Ala-OH)or either protected (PMB or Bn) or unprotected enantiomer of ethyllactate.

Example 1: Preparation of(S)-2-(benzyloxy)-1,1-bis(4-fluorophenyl)propan-1-ol

To a solution of (S)-ethyl 2-(benzyloxy)propanoate (2.08 grams (g), 10.0millimoles (mmol)) in tetrahydrofuran (THF; 20 milliliters (mL)) at 0°C. was slowly added (4-fluorophenyl)magnesium bromide (31.3 mL, 25.0mmol, 0.8 molar (M) in THF) over a 10 minute (min) period. The reactionvessel was allowed to warm slowly to room temperature over 2 hours (h),and the reaction mixture was quenched by careful addition of saturated(sat.) aqueous (aq.) ammonium chloride (NH₄Cl; 50 mL). The mixture wasdiluted with diethyl ether (Et₂O; 50 mL), the phases were separated, andthe aq. phase was extracted with Et₂O (2×50 mL). The combined organicphases were washed with sat. aq. sodium chloride (NaCl, brine; 100 mL),dried over sodium sulfate (Na₂SO₄), filtered, and concentrated. Theresulting oil was purified by flash column chromatography (silica gel(SiO₂), 0→5% acetone in hexanes) to afford the title compound (3.28 g,93%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 7.47-7.38 (m, 2H),7.38-7.27 (m, 5H), 7.17-7.09 (m, 2H), 7.04-6.89 (m, 4H), 4.64 (dd,J=11.4, 0.7 Hz, 1H), 4.51-4.38 (m, 2H), 3.12 (s, 1H), 1.11 (d, J=6.1 Hz,3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −116.19, −116.41; ESIMS m/z 377([M+Na]⁺).

Example 2A: Preparation of(S)-4,4′-(2-(benzyloxy)propane-1,1-diyl)bis(fluorobenzene)

To a solution of (S)-2-(benzyloxy)-1,1-bis(4-fluorophenyl)propan-1-ol(709 milligrams (mg), 2.00 mmol) in dichloromethane (DCM; 20 mL) at 0°C. was added triethylsilane (Et₃SiH; 3.19 mL, 20.0 mmol) followed by2,2,2-trifluoroacetic acid (TFA; 1.53 mL, 20.0 mmol). The mixture wasstirred at 0° C. for 1 h. The resulting solution was quenched by carefuladdition of sat. aq. sodium bicarbonate (NaHCO₃; 20 mL). The phases wereseparated, and the aq. phase was extracted with DCM (2×30 mL). Thecombined organic phases were washed with brine (50 mL), dried overNa₂SO₄, filtered, and concentrated. The resulting oil was purified byflash column chromatography (SiO₂, 0→10% acetone in hexanes) to affordthe title compound (627 mg, 92%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.31-7.22 (m, 5H), 7.21-7.16 (m, 2H), 7.10-7.03 (m, 2H),7.00-6.91 (m, 4H), 4.54 (dd, J=11.5, 0.7 Hz, 1H), 4.31 (dd, J=11.6, 0.8Hz, 1H), 4.14 (dq, J=8.1, 6.1 Hz, 1H), 3.93 (d, J=8.1 Hz, 1H), 1.18 (d,J=6.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −116.60, −117.10; ESIMS (m/z)361 ([M+Na]⁺).

Example 2B: Preparation of(S)-(2-(benzyloxy)-1-methoxypropane-1,1-diyl)dibenzene

To a suspension of sodium hydride (NaH; 52.0 mg, 1.30 mmol, 60% weightper weight (w/w) in mineral oil) in N,N-dimethylformamide (DMF; 3 mL) at0° C. was added a solution of (S)-2-(benzyloxy)-1,1-diphenylpropan-1-ol(318 mg, 1 mmol) in DMF (1 mL). The reaction mixture was stirred at roomtemperature for 30 min and then cooled to 0° C. Iodomethane (MeI; 93.0microliters (μL), 1.50 mmol) was added, and the reaction mixture wasstirred at room temperature for 1 h. The resulting solution was quenchedby careful addition of sat. aq. NaHCO₃ (10 mL). The mixture was dilutedwith diethyl ether (Et₂O; 10 mL), the phases were separated, and the aq.phase was extracted with Et₂O (2×10 mL). The combined organic phaseswere washed with brine (20 mL), dried over Na₂SO₄, filtered, andconcentrated. The resulting oil was purified by flash columnchromatography (SiO₂, 0→5% acetone in hexanes) to afford the titlecompound (295 mg, 89%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ7.47-7.41 (m, 2H), 7.40-7.35 (m, 2H), 7.33-7.18 (m, 11H), 4.69 (d,J=11.9 Hz, 1H), 4.54 (d, J=12.3 Hz, 1H), 4.50 (q, J=6.1 Hz, 1H), 3.13(s, 3H), 1.10 (d, J=6.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 142.96,141.31, 138.79, 129.13, 128.54, 128.14, 127.61, 127.16, 127.08, 126.95,126.69, 99.99, 85.35, 78.13, 70.80, 52.46, 13.65; ESIMS (m/z) 333([M+H]⁺).

Example 2C: Preparation of(S)-(2-(benzyloxy)-1-fluoropropane-1,1-diyl)dibenzene

To a solution of (S)-2-(benzyloxy)-1,1-diphenylpropan-1-ol (300 mg,0.942 mmol) in DCM (5 mL) at 0° C. was added (diethylamino)sulfurtrifluoride (DAST; 1.88 mL, 1.88 mmol, 1 M in DCM). The reaction wasslowly warmed to room temperature over 3 h. The resulting solution wasquenched by careful addition of sat. aq. NaHCO₃ (5 mL). The phases wereseparated, and the aq. phase was extracted with DCM (2×10 mL). Thecombined organic phases were washed with brine (10 mL), dried overNa₂SO₄, filtered, and concentrated. The resulting oil was purified byflash column chromatography (SiO₂, 0→10% acetone in hexanes) to affordthe title compound (300 mg, 98%) as a colorless oil: ¹H NMR (400 MHz,CDCl₃) δ 7.58-7.49 (m, 2H), 7.43-7.37 (m, 2H), 7.36-7.20 (m, 9H),7.09-6.99 (m, 2H), 4.47 (d, J=11.7 Hz, 1H), 4.37-4.25 (m, 2H), 1.26 (dd,J=6.3, 1.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 142.23 (d, J=22.7 Hz),141.00 (d, J=23.5 Hz), 138.03, 128.21, 128.16, 127.90 (d, J=1.5 Hz),127.80, 127.72 (d, J=1.7 Hz), 127.52, 127.42 (d, J=1.3 Hz), 126.23 (d,J=9.6 Hz), 125.93 (d, J=8.7 Hz), 99.96 (d, J=180.8 Hz), 78.91 (d, J=26.9Hz), 71.68, 14.47 (d, J=3.6 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −159.80.

Example 2D, Step 1: Preparation of(S)—O-(2-(benzyloxy)-1,1-bis(3,4,5-trifluorophenyl)propyl)S-methylcarbonodithioate

To a solution of(S)-2-(benzyloxy)-1,1-bis(3,4,5-trifluorophenyl)propan-1-ol (496 mg,1.16 mmol) in anhydrous THF (5.8 mL) was added NaH (93.0 mg, 2.33 mmol),followed by imidazole (3.96 mg, 0.0580 mmol), and the reaction mixturewas stirred at ambient temperature for 1 h. Carbon disulfide (562 μL,9.30 mmol) was added via syringe in one portion, followed by MeI (579μL, 9.30 mmol), and the reaction mixture was stirred at ambienttemperature for 2 h. The reaction mixture was diluted with Et₂O (5 mL)and quenched with sat. aq. NH₄Cl (10 mL). The layers were separated, andthe aq. layer was extracted with Et₂O (3×10 mL). The combined organiclayers were dried over magnesium sulfate (MgSO₄), filtered andconcentrated to afford an orange/brown oil. The crude oil was purifiedby flash column chromatography (SiO₂, 0→50% ethyl acetate (EtOAc) inhexanes) to afford the title compound (627 mg, 94%) as a clear, brightyellow colored oil: ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.27 (m, 3H),7.24-7.16 (m, 2H), 7.02 (dd, J=9.1, 6.6 Hz, 2H), 6.96 (dd, J=8.8, 6.5Hz, 2H), 5.44 (q, J=6.1 Hz, 1H), 4.66 (d, J=11.6 Hz, 1H), 4.51 (d,J=11.6 Hz, 1H), 2.49 (s, 3H), 1.16 (d, J=6.1 Hz, 3H); ¹⁹F NMR (376 MHz,CDCl₃) δ −133.89 (d, J=20.7 Hz), −134.73 (d, J=20.6 Hz), −159.83 (t,J=20.6 Hz), −160.56 (t, J=20.7 Hz); (Thin film) 2922, 1721, 1622, 1595,1526, 1436, 1344, 1241, 1217, 1197, 1119, 1088, 1040, 965, 908, 861,822, 730, 712, 697, 672 cm⁻¹.

Example 2D, Step 2: Preparation of(S)-5,5′-(2-(benzyloxy)propane-1,1-diyl)bis(1,2,3-trifluorobenzene)

A solution of(S)—O-(2-(benzyloxy)-1,1-bis(3,4,5-trifluorophenyl)propyl)S-methylcarbonodithioate (598 mg, 1.16 mmol) in toluene (200 mL) was degassed bya freeze-pump-thaw procedure (3 cycles using liquid nitrogen (N₂)) underan atmosphere of N₂. Tributyltin hydride (3.12 mL, 11.6 mmol) was thenadded, the reaction flask was fitted with a reflux condenser, and thereaction mixture was heated to a light reflux (115° C.). A solution ofazobisisobutyronitrile (AIBN; 0.200 g, 1.22 mmol) in degassed toluene (3cycles via liquid N₂; 32 mL) was added via syringe down the refluxcondenser over 3 h. Once slow addition of the AIBN was complete, thereaction mixture was stirred at reflux overnight. The solvent wasremoved in vacuo to provide a pale yellow oil. The crude oil waspurified by flash column chromatography (SiO₂, 0→30% EtOAc in hexanes)to afford the title compound (358 mg, 72%) as a clear, colorless oil: ¹HNMR (400 MHz, CDCl₃) δ 7.28 (d, J=6.6 Hz, 3H), 7.17-7.06 (m, 2H), 6.92(dd, J=8.5, 6.5 Hz, 2H), 6.79 (dd, J=8.3, 6.4 Hz, 2H), 4.59 (d, J=11.7Hz, 1H), 4.31 (d, J=11.7 Hz, 1H), 4.02 (p, J=6.2 Hz, 1H), 3.76 (d, J=6.8Hz, 1H), 1.19 (d, J=6.1 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −133.80 (d,J=20.5 Hz), −134.34 (d, J=20.5 Hz), −162.54 (t, J=20.5 Hz), −162.84 (t,J=20.5 Hz); (Thin film) 2871, 1621, 1526, 1445, 1345, 1262, 1235, 1116,1096, 1043, 859, 802, 728, 698, 679 cm⁻¹.

Example 3A: Preparation of (S)-1,1-bis(4-fluorophenyl)propan-2-ol

To a solution of(S)-4,4′-(2-(benzyloxy)propane-1,1-diyl)bis(fluorobenzene) (575 mg, 1.70mmol) in ethanol (EtOH; 11 mL) and cyclohexene (5.5 mL) at roomtemperature was added palladium on carbon (Pd/C; 362 mg, 0.0850 mmol,2.5% w/w of Pd). The reaction mixture was stirred at 65° C. for 2 h,cooled to room temperature, filtered through a plug of Celite®, andconcentrated to afford the title compound (415 mg, 98%) as a colorlessoil: ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.29 (m, 2H), 7.25-7.18 (m, 2H),7.09-6.93 (m, 4H), 4.47 (dqd, J=8.2, 6.1, 3.3 Hz, 1H), 3.80 (d, J=8.3Hz, 1H), 1.55 (d, J=3.3 Hz, 1H), 1.19 (d, J=6.1 Hz, 3H); ¹³C NMR (101MHz, CDCl₃) δ 162.90 (d, J=23.3 Hz), 160.46 (d, J=23.1 Hz), 138.15 (d,J=3.1 Hz), 136.94 (d, J=3.6 Hz), 130.14 (d, J=7.8 Hz), 129.55 (d, J=7.8Hz), 115.70 (d, J=18.8 Hz), 115.49 (d, J=18.8 Hz), 70.07, 58.61, 21.63;¹⁹F NMR (376 MHz, CDCl₃) δ −115.84, −116.19.

Example 3B: Preparation of (S)-1,1-bis(2-fluorophenyl)propane-1,2-diol

To a solution of(S)-1,1-bis(2-fluorophenyl)-2-((4-methoxybenzyl)oxy)propan-1-ol (790 mg,2.06 mmol) in DCM (20 mL) at 0° C. was added Et₃SiH (3.28 mL, 20.6 mmol)followed by TFA (1.57 mL, 20.6 mmol). The mixture was stirred at 0° C.for 1 h. The resulting solution was quenched by careful addition of sat.aq. NaHCO₃ (20 mL). The phases were separated, and the aq. phase wasextracted with DCM (2×30 mL). The combined organic phases were washedwith brine (50 mL), dried over Na₂SO₄, filtered, and concentrated. Theresulting oil was purified by flash column chromatography (SiO₂, 0→10%acetone in hexanes) to afford the title compound (388 mg, 71%) as acolorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.90-7.77 (m, 1H), 7.70 (tt,J=8.2, 1.5 Hz, 1H), 7.31-7.10 (m, 4H), 6.97 (ddd, J=12.7, 8.1, 1.3 Hz,1H), 6.88 (ddd, J=11.8, 8.0, 1.4 Hz, 1H), 5.11 (qd, J=6.3, 2.3 Hz, 1H),3.49 (s, 1H), 2.27 (s, 1H), 1.09 (d, J=6.3 Hz, 3H); ¹⁹F NMR (376 MHz,CDCl₃) δ −112.90 (d, J=8.3 Hz), −113.92 (d, J=8.4 Hz); ESIMS (m/z) 551([2M+Na]⁺).

Example 3C: Preparation of (S)-1,1-bis(4-bromophenyl)propan-2-ol

To a solution of(S)-1,1-bis(4-bromophenyl)-2-((4-methoxybenzyl)oxy)propan-1-ol (1.80 g,3.56 mmol) in DCM (18 mL) at 0° C. was added Et₃SiH (5.68 mL, 35.6 mmol)followed by TFA (2.72 mL, 35.6 mmol). The mixture was warmed slowly toroom temperature over 3 h. The resulting solution was quenched bycareful addition of sat. aq. NaHCO₃ (20 mL). The phases were separated,and the aq. phase was extracted with DCM (2×30 mL). The combined organicphases were washed with brine (50 mL), dried over Na₂SO₄, filtered, andconcentrated. The resulting oil was purified by flash columnchromatography (SiO₂, 0→10% acetone in hexanes) to afford the titlecompound (742 mg, 56%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ7.51-7.36 (m, 4H), 7.25-7.17 (m, 2H), 7.18-7.06 (m, 2H), 4.48 (dq,J=8.2, 6.1 Hz, 1H), 3.76 (d, J=8.2 Hz, 1H), 2.80 (s, 1H), 1.19 (d, J=6.2Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 140.94, 139.85, 131.98, 131.85,130.39, 129.84, 121.06, 120.72, 69.82, 58.91, 21.65; (Thin film) 3390,3024, 2969, 2900, 1486, 1072 cm⁻¹.

Example 3D, Step 1: Preparation of(S)-1,1-bis(4-((trimethylsilyl)ethynyl)-phenyl)propan-2-ol

To a solution of (S)-1,1-bis(4-bromophenyl)propan-2-ol (1.01 g, 2.72mmol) in THF (9 mL) was added bis(triphenylphosphine)palladiumdichloride (0.095 g, 0.136 mmol) and copper(I) iodide (CuI; 0.026 g,0.136 mmol). The mixture was sparged with N₂ for 20 min, andtriethylamine (Et₃N; 4.53 mL) was added dropwise. To the resultingmixture was added ethynyltrimethylsilane (1.15 mL, 8.15 mmol) dropwise,and the mixture was heated to reflux and stirred overnight. The mixturewas cooled to room temperature, and the reaction was quenched with sat.aq. NaHCO₃. The products were extracted with EtOAc (2×), and thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude residue was then purified by flashcolumn chromatography (SiO₂, 0→20% acetone in hexanes) to provide thetitle compound (495 mg, 45%) as a brown foam: ¹H NMR (400 MHz, CDCl₃) δ7.48-7.42 (m, 2H), 7.42-7.37 (m, 2H), 7.33-7.27 (m, 2H), 7.24-7.17 (m,2H), 4.51 (dqd, J=12.2, 6.1, 3.5 Hz, 1H), 3.81 (d, J=8.3 Hz, 1H), 1.60(d, J=3.8 Hz, 1H), 1.18 (d, J=6.1 Hz, 3H), 0.26 (s, 9H), 0.26 (s, 9H);¹³C NMR (101 MHz, CDCl₃) δ 142.55, 141.48, 132.42, 132.29, 128.69,128.15, 121.90, 121.57, 104.76, 104.71, 94.49, 94.33, 69.76, 59.96,21.55, 0.00; (Thin film) 3397, 2960, 2156, 1501, 1248, 861, 840 cm⁻¹,HRMS-ESI (m/z) [M+H]⁺ calcd for C₂₅H₃₃OSi₂, 405.2064; found, 405.2070.

Example 3D, Step 2: Preparation of(S)-1,1-bis(4-ethynylphenyl)propan-2-ol

To a solution of(S)-1,1-bis(4-((trimethylsilyl)ethynyl)phenyl)propan-2-ol (0.470 g, 1.16mmol) in methanol (MeOH; 5.8 mL) was added potassium carbonate (K₂CO₃;0.482 g, 3.48 mmol). The mixture was stirred for 1 h at room temperatureand then filtered through Celite®. The filter cake was washed with MeOH,and the filtrate was concentrated. The crude material was purified byflash column chromatography (SiO₂, 0→20% acetone in hexanes) to providethe title compound (288 mg, 95%) as a yellow oil: ¹H NMR (300 MHz,CDCl₃) δ 7.48-7.43 (m, 2H), 7.43-7.39 (m, 2H), 7.35-7.29 (m, 2H),7.24-7.19 (m, 2H), 4.51 (dqd, J=8.3, 6.1, 3.7 Hz, 1H), 3.82 (d, J=8.3Hz, 1H), 3.05 (s, 1H), 3.04 (s, 1H), 1.63-1.55 (m, 1H), 1.18 (d, J=6.1Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 142.84, 141.82, 132.60, 132.48,128.74, 128.22, 120.87, 120.57, 83.31, 83.29, 77.39, 77.29, 69.73,59.96, 21.66; (Thin film) 3436, 3280, 2968, 2106, 1499, 1075, 825 cm⁻¹;HRMS-ESI (m/z) [M+H]⁺ calcd for C₁₉H₁₇O, 261.1274; found, 261.1272.

Example 3D, Step 3: Preparation of (S)-1,1-bis(4-ethylphenyl)propan-2-ol

To a solution of (S)-1,1-bis(4-ethynylphenyl)propan-2-ol (0.144 g, 0.553mmol) in EtOAc (2.8 mL) was added palladium (5% weight (wt) on carbon,dry basis; 0.235 g, 0.055 mmol). The mixture was stirred under a balloonof hydrogen overnight. The mixture was filtered through Celite®, and thefilter cake was washed with EtOAc. The combined filtrate was thenconcentrated, and the crude residue was purified by flash columnchromatography (SiO₂, 0→25% acetone in hexanes) to provide the titlecompound (97.0 mg, 65%) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ7.33-7.25 (m, 2H), 7.22-7.15 (m, 2H), 7.18-7.11 (m, 2H), 7.10 (d, J=8.1Hz, 2H), 4.51 (dqd, J=8.7, 6.1, 2.5 Hz, 1H), 3.74 (d, J=8.9 Hz, 1H),2.65-2.53 (m, 4H), 1.68 (d, J=2.8 Hz, 1H), 1.23-1.14 (m, 9H); ¹³C NMR(101 MHz, CDCl₃) δ 142.74, 142.33, 139.94, 138.91, 128.48, 128.40,128.07, 128.02, 70.19, 60.02, 28.41, 28.39, 21.37, 15.47, 15.46; (Thinfilm) 3421, 2963, 1510, 1110, 821 cm⁻¹; HRMS-ESI (m/z) ([M+Na]⁺) calcdfor C₁₉H₂₄NaO, 291.1719; found, 291.1725.

Example 3E: Preparation of 1-(9H-xanthen-9-yl)ethanol

To a solution of 9H-xanthene (364 mg, 2.00 mmol) in THF (10 mL) at −78°C. was added n-butyllithium (2.5 M in hexanes; 0.880 mL, 2.20 mmol). Themixture was stirred at −78° C. for 30 min. Acetaldehyde (0.226 mL, 4.00mmol) was added, and the reaction mixture was warmed slowly to roomtemperature overnight. The resulting solution was quenched by carefuladdition of sat. aq. NH₄Cl (10 mL). The phases were separated, and theaq. phase was extracted with Et₂O (2×15 mL). The combined organic phaseswere washed with brine (20 mL), dried over Na₂SO₄, filtered, andconcentrated. The resulting oil was purified by flash columnchromatography (SiO₂, 0→10% acetone in hexanes) to afford the titlecompound (216 mg, 48%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ7.33-7.22 (m, 4H), 7.17-7.04 (m, 4H), 3.99 (d, J=5.1 Hz, 1H), 3.96-3.82(m, 1H), 1.54 (d, J=6.0 Hz, 1H), 1.00 (d, J=6.3 Hz, 3H); ¹³C NMR (101MHz, CDCl₃) δ 152.94, 152.65, 129.54, 129.30, 128.19, 128.17, 123.18,123.14, 122.48, 121.73, 116.59, 116.41, 73.07, 47.06, 18.81; ESIMS (m/z)475 ([2M+Na]⁺).

Example 3F: Preparation of(1S,2S)-1-phenyl-1-(4-(trifluoromethyl)phenyl)propan-2-ol

To a mixture of magnesium turnings (102 mg, 4.20 mmol) in Et₂O (4 mL)was added 1-bromo-4-(trifluoromethyl)benzene (0.588 mL, 4.20 mmol) atroom temperature, followed by MeI (5 μL). Upon warming to a gentle boilusing a heat gun, the mixture turned a yellow/brown color. The reactionwas then stirred in a water bath at room temperature for 30 min untilalmost all the magnesium was consumed. This was added to a suspension ofcopper(I) iodide (CuI; 400 mg, 2.10 mmol) in Et₂O (4 mL) at −78° C. Thereaction was stirred at −20° C. for 30 min, then cooled to −78° C., and(2S,3S)-2-methyl-3-phenyloxirane (0.201 mL, 1.50 mmol) was added. Theresulting mixture was warmed slowly to room temperature overnight. Theresulting solution was quenched by careful addition of sat. aq. NH₄Cl(10 mL). The phases were separated, and the aq. phase was extracted withEt₂O (2×15 mL). The combined organic phases were washed with brine (20mL), dried over Na₂SO₄, filtered, and concentrated. The resulting oilwas purified by flash column chromatography (SiO₂, 0→10% acetone inhexanes) to afford the title compound (390 mg, 94%) as a light yellowoil: ¹H NMR (400 MHz, CDCl₃) δ 7.60-7.50 (m, 2H), 7.48-7.38 (m, 2H),7.38-7.33 (m, 4H), 7.30-7.23 (m, 1H), 4.58 (dqd, J=8.4, 6.1, 3.5 Hz,1H), 3.88 (d, J=8.5 Hz, 1H), 1.65 (d, J=3.6 Hz, 1H), 1.20 (d, J=6.1 Hz,3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −62.49; ESIMS (m/z) 263 ([M−OH]⁺).

Example 3G, Step 1: Preparation of4,4′-(2-oxopropane-1,1-diyl)dibenzonitrile

To a suspension of 4-bromobenzonitrile (546 mg, 3.00 mmol) and cesiumcarbonate (977 mg, 3.00 mmol) in THF (10 mL) under an N₂ atmosphere wasadded acetone (1.10 mL, 15.00 mmol), followed by X-Phos Pd G3 (50.8 mg,0.060 mmol). Then, the vial was sealed and heated to 55° C. for 4 days.The reaction was diluted with EtOAc (30 mL) and washed with sat. NH₄Cl(3×10 mL), water (15 mL), and brine (15 mL). Then the organic phase wasdried over Na₂SO₄, filtered, and concentrated. The resulting oil waspurified by flash column chromatography (SiO₂, 0→40% EtOAc in hexanes)to afford the title compound (174 mg, 22%) as a colorless oil: ¹H NMR(400 MHz, CDCl₃) δ 7.66 (d, J=8.4 Hz, 4H), 7.34 (d, J=8.3 Hz, 4H), 5.21(s, 1H), 2.29 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 203.68, 142.15,132.75, 129.64, 118.21, 112.00, 64.25, 30.43; ESIMS m/z 261 ([M+H]⁺).

Example 3G, Step 2: Preparation of(S)-4,4′-(2-hydroxypropane-1,1-diyl)dibenzonitrile

To a solution of 4,4′-(2-oxopropane-1,1-diyl)dibenzonitrile (174 mg,0.668 mmol) in toluene (4.5 mL) was added(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (1 Msolution in toluene, 66.8 μL, 0.067 mmol). Then, the reaction was cooledto 0° C. and a solution of BH₃-DMS (69.8 μl, 0.735 mmol) in 0.5 mLtoluene was added over 2 min. The flask was left to stir at 0° C. After2 h, the reaction was quenched with methanol (0.5 mL), diluted withEtOAc and added water. Phases were separated and the aqueous phase wasextracted with EtOAc×2. The combined organic phases were washed withbrine (20 mL), dried over Na₂SO₄, filtered, and concentrated. Theresulting oil was purified by flash column chromatography (SiO₂, 0→50%EtOAc in hexanes) to afford the title compound (99.7 mg, 57%) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (dd, J=8.4, 6.8 Hz, 4H),7.51-7.46 (m, 2H), 7.43-7.37 (m, 2H), 4.63-4.47 (m, 1H), 3.97 (d, J=7.5Hz, 1H), 1.97 (d, J=3.8 Hz, 1H), 1.21 (d, J=6.2 Hz, 3H). ¹³C NMR (101MHz, CDCl₃) δ 146.91, 145.86, 132.60, 132.45, 129.90, 129.19, 118.58,118.51, 110.96, 110.92, 69.19, 59.56, 22.27; ESIMS m/z 263 ([M+H]⁺).

Example 3H, Step 1: Preparation of 3,3-diphenylbutan-2-one

To a magnetically stirred mixture of 2,3-diphenylbutane-2,3-diol (500mg, 2.06 mmol) in DCM (10 mL) was added antimony pentachloride (26.5 μL,0.206 mmol) under air atmosphere. The reaction mixture was stirred at25° C. for 1 h and then was quenched by slow addition of sat. aq.NaHCO₃. The resulting mixture was diluted with water and additional DCM,and the organic layer was separated by passing through a phaseseparator. The resulting oil was purified by flash column chromatography(SiO₂, 0→5% acetone in hexanes) to afford the title compound (330 mg,71%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.31 (m, 4H),7.30-7.25 (m, 2H), 7.23-7.15 (m, 4H), 2.11 (s, 3H), 1.87 (s, 3H); ¹³CNMR (101 MHz, CDCl₃) δ 209.16, 143.59, 128.36, 126.91, 62.32, 27.62,26.42; ESIMS m/z 225 ([M+H]⁺).

Example 3H, Step 2: Preparation of (S)-3,3-diphenylbutan-2-ol

To a solution of 3,3-diphenylbutan-2-one (150 mg, 0.669 mmol) in toluene(4.5 mL) was added(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (1 Msolution in toluene, 134 μL, 0.134 mmol). Then, a solution of BH₃-DMS(70.2 μL, 0.702 mmol) in 0.5 mL of toluene was added to the reactionmixture over 2 min. The flask was left to stir at room temperature.After 1 h, the reaction was quenched with methanol (0.5 mL). DCM andwater were added, and the phases were separated. The aqueous phase wasextracted with DCM (2×). The combined organic phases were washed withbrine (20 mL), dried over Na₂SO₄, filtered, and concentrated. Theresulting oil was purified by flash column chromatography (SiO₂, 0→20%acetone in hexanes) to afford the title compound (150 mg, 99%) as acolorless oil: ¹H NMR (400 MHz, CDCl₃) δ d 7.39-7.17 (m, 10H), 4.70-4.61(m, 1H), 1.67 (s, 3H), 1.51 (d, J=4.9 Hz, 1H), 1.11 (d, J=6.3 Hz, 3H);¹³C NMR (101 MHz, CDCl₃) δ 147.30, 145.86, 128.40, 128.15, 128.05,127.79, 126.20, 126.01, 72.28, 51.77, 23.26, 18.39; ESIMS m/z 227([M+H]⁺).

Example 31, Step 1: Preparation of(S)-1,1-bis(2,3-dimethoxyphenyl)propane-1,2-diol

To a solution of isopropylmagnesium lithium chloride (1.3 M in THF, 6.1mL, 8.00 mmol) was added THF (2 mL) and 1-bromo-2,3-dimethoxybenzene(1.74 g, 8.00 mmol). The resulting brown solution was heated to a gentlereflux (75° C. external temp) for 2.5 h, then cooled to 0° C. in an icewater bath. (S)-methyl 2-hydroxypropanoate (0.191 ml, 2 mmol) was thenadded dropwise via syringe. The reaction was stirred at 0° C. for 1 h,then removed from the cold bath and stirred overnight at rt. Thereaction was cooled to 0° C. in an ice water bath, diluted with water(20 mL), brine (20 mL), and Et₂O (40 mL), and was quenched with 1 N HCl(8 mL). The phases were separated, and the aqueous phase was extractedwith Et₂O (20 mL). The organic phases were combined, dried over MgSO₄,filtered, and concentrated to provide an oil. Purification by automatedsilica gel column chromatography (5-50% EtOAc in hexanes) provided thetitle compound (568 mg, 82%) as a yellow, crystalline solid: ¹H NMR (300MHz, CDCl₃) δ 7.43 (td, J=8.0, 1.5 Hz, 2H), 7.11 (td, J=8.1, 4.9 Hz,2H), 6.83 (dd, J=8.1, 1.4 Hz, 2H), 5.06-4.82 (m, 1H), 4.74 (d, J=1.2 Hz,1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.20 (s, 3H), 3.04 (s, 3H), 2.86 (d,J=9.5 Hz, 1H), 0.97 (d, J=6.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ152.89, 152.82, 146.94, 145.53, 139.56, 138.92, 123.32, 123.26, 122.01,119.01, 111.30, 79.20, 77.22, 60.07, 59.26, 55.77, 55.64, 18.34;HRMS-ESI (m/z) ([M+Na]⁺) calcd for C₁₉H₂₄O₆Na, 371.1465; found,371.1456.

Example 31, Step 2: Preparation of1,1-bis(2,3-dimethoxyphenyl)propan-2-one

To a solution of (S)-1,1-bis(2,3-dimethoxyphenyl)propane-1,2-diol (560mg, 1.61 mmol) in anhydrous CH₂Cl₂ (8 mL) at 0° C. was addedtriethylsilane (770 μl, 4.82 mmol) and trifluoroacetic acid (TFA, 124μL, 1.61 mmol). The resulting solution was stirred at 0° C. for 2 h,then removed from the cold bath and stirred for 2 h. TFA (248 μL, 3.2mmol) was added, and the reaction was then stirred overnight at rt. Thereaction was diluted with water (25 mL) and extracted with CH₂Cl₂ (3×25mL). The organic extracts were dried over Na₂SO₄, filtered, andconcentrated to provide an oil. Purification by automated silica gelcolumn chromatography (5-25% acetone in hexanes) provided the titlecompound (396 mg, 75%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 6.99(t, J=8.0 Hz, 2H), 6.87 (dd, J=8.2, 1.5 Hz, 2H), 6.67-6.54 (m, 2H), 5.86(s, 1H), 3.87 (s, 6H), 3.75 (s, 6H), 2.25 (s, 3H); ¹³C NMR (126 MHz,CDCl₃) δ 207.18, 152.69, 147.02, 132.23, 123.74, 121.61, 111.64, 60.36,55.74, 51.96, 29.80; HRMS-ESI (m/z) ([M+Na]⁺) calcd for C₁₉H₂₂O₅Na,353.1359; found, 353.1353.

Example 31, Step 3: Preparation of1,1-bis(2,3-dimethoxyphenyl)propan-2-ol

To a solution of 1,1-bis(2,3-dimethoxyphenyl)propan-2-one (356 mg, 1.08mmol) in methanol (3.5 mL) was added sodium borohydride (61 mg, 1.6mmol). The resulting solution was stirred at rt for 20 h, then wasquenched with sat'd NH₄Cl (1 mL), diluted with water (20 mL) andextracted with CH₂Cl₂ (3×20 mL). The organic extracts were combined,dried over Na₂SO₄, filtered, and concentrated to provide the titlecompound (360 mg, 100%) as an oil: ¹H NMR (300 MHz, CDCl₃) δ 7.16-6.88(m, 4H), 6.79 (ddd, J=9.6, 7.8, 1.9 Hz, 2H), 4.81 (d, J=8.3 Hz, 1H),4.53-4.32 (m, 1H), 3.84 (s, 3H), 3.84 (s, 3H), 3.77 (s, 3H), 3.76 (s,3H), 2.04 (d, J=4.2 Hz, 1H), 1.22 (d, J=6.2 Hz, 3H); ¹³C NMR (126 MHz,CDCl₃) δ 152.98, 152.83, 147.71, 147.04, 136.17, 135.33, 123.94, 123.62,120.96, 120.84, 110.76, 110.48, 70.32, 60.26, 60.20, 55.66, 55.63,45.11, 21.80; IR (neat film) 3451, 2935, 2833, 1582, 1473, 1428, 1266,1215, 1167, 1125, 1088, 1068, 1004, 964, 908, 835, 809, 787, 748, 728.

Example 4A: Preparation of (S)—(S)-1,1-diphenylpropan-2-yl2-((tert-butoxycarbonyl)amino)-propanoate

To a solution of (S)-1,1-diphenylpropan-2-ol (317 mg, 1.493 mmol) in DCM(15 mL) at 0° C. were added (S)-2-((tert-butoxycarbonyl)amino)propanoicacid (Boc-Ala-OH; 311 mg, 1.64 mmol) and N,N-dimethylpyridin-4-amine(DMAP; 18.2 mg, 0.149 mmol) followed byN¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (EDC; 573 mg, 2.99 mmol), and the reaction mixture wasstirred at room temperature overnight and concentrated to give a yellowoil. The crude material was purified by flash column chromatography(SiO₂, 1→10% acetone in hexanes) to afford the title compound (433 mg,75%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.07 (m, 10H),5.80 (dq, J=10.1, 6.1 Hz, 1H), 4.97 (d, J=8.0 Hz, 1H), 4.19-4.06 (m,1H), 4.03 (d, J=10.1 Hz, 1H), 1.41 (s, 9H), 1.23 (d, J=6.1 Hz, 3H), 0.76(d, J=7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 172.83, 154.96, 141.52,141.26, 128.79, 128.50, 128.10, 128.08, 126.91, 126.67, 79.62, 73.10,57.98, 49.21, 28.33, 19.31, 17.98; ESIMS m/z 384 ([M+H]⁺).

Example 5, Step 1: Preparation of(S)-1-(((S)-1,1-diphenylpropan-2-yl)oxy)-1-oxopropan-2-aminium chloride

To a solution of (S)—(S)-1,1-diphenylpropan-2-yl2-((tert-butoxycarbonyl)amino)propanoate (Cmpd 2; 433 mg, 1.13 mmol) inDCM (6 mL) was added a 4 N solution of HCl in dioxane (2.8 mL, 11.3mmol), and the mixture was stirred for 3 h at room temperature. Thesolvent was evaporated under a stream of N₂ to provide the titlecompound (360 mg, 100%) as a white solid: ESIMS (m/z) 284 ([M+H]⁺).

Example 5, Step 2: Preparation of (S)—(S)-1,1-diphenylpropan-2-yl2-(3-hydroxy-4-methoxypicolinamido)propanoate

To a solution of(S)-1-(((S)-1,1-diphenylpropan-2-yl)oxy)-1-oxopropan-2-aminium chloride(Cmpd 46; 361 mg, 1.13 mmol) and 3-hydroxy-4-methoxypicolinic acid (210mg, 1.24 mmol) in DCM (11 mL) were addedbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP; 646 mg, 1.24 mmol) and N-ethyl-N-isopropylpropan-2-amine (DIPEA;0.651 mL, 3.72 mmol), and the reaction mixture was stirred for 2 h atroom temperature. The solvent was evaporated and the crude oil waspurified by flash column chromatography (SiO₂, 1→50% acetone in hexanes)to afford the title compound (340 mg, 70%) as a white foam: ¹H NMR (400MHz, CDCl₃) δ 12.10 (s, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.98 (d, J=5.2 Hz,1H), 7.38-7.06 (m, 10H), 6.86 (d, J=5.3, 1H), 5.83 (dq, J=10.1, 6.1 Hz,1H), 4.52 (dq, J=8.1, 7.2 Hz, 1H), 4.06 (d, J=10.2 Hz, 1H), 3.93 (s,3H), 1.26 (d, J=6.1 Hz, 3H), 0.97 (d, J=7.2 Hz, 3H); ¹³C NMR (101 MHz,CDCl₃) δ 171.67, 168.53, 155.34, 148.72, 141.38, 141.13, 140.40, 130.48,128.80, 128.50, 128.10, 128.03, 126.95, 126.70, 109.39, 73.57, 57.93,56.07, 47.85, 19.24, 17.61; HRMS-ESI (m/z) ([M+H]⁺) calcd forC₂₅H₂₇N₂O₅, 435.1920; found, 435.1925.

Example 6A: Preparation of (S)—(S)-1,1-diphenylpropan-2-yl2-(3-acetoxy-4-methoxypicolinamido)propanoate

To a solution of (S)—(S)-1,1-diphenylpropan-2-yl2-(3-hydroxy-4-methoxypicolinamido)-propanoate (Cmpd 90; 70.0 mg, 0.161mmol), Et₃N (44.9 μL, 0.332 mmol), and DMAP (3.94 mg, 0.032 mmol) in DCM(3.2 mL) was added acetyl chloride (17.2 μL, 0.242 mmol) at roomtemperature, and the reaction mixture was stirred for 2 h. The solventwas evaporated, and the resulting crude oil was purified by flash columnchromatography (SiO₂, 1→40% acetone in hexanes) to afford the titlecompound (75.0 mg, 97%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ8.41 (d, J=7.8 Hz, J H), 8.30 (d, J=5.4 Hz, 1H), 7.38-7.10 (m, 10H),6.97 (d, J=5.4 Hz, 1H), 5.82 (dq, J=10.0, 6.2 Hz, 1H), 4.52 (dt, J=8.2,7.1 Hz, 1H), 4.05 (d, J=10.1 Hz, 1H), 3.87 (s, 3H), 2.37 (s, 3H), 1.24(d, J=6.1 Hz, 3H), 0.89 (d, J=7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ172.23, 168.89, 162.28, 159.42, 146.66, 141.55, 141.44, 141.25, 137.45,128.77, 128.50, 128.13, 128.11, 126.89, 126.67, 109.73, 73.32, 57.90,56.27, 47.85, 20.75, 19.25, 17.92; HRMS-ESI (m/z) ([M+H]⁺) calcd forC₂₇H₂₉N₂O₆, 477.2025; found, 477.2019.

Example 6B: Preparation of (S)—(S)-1,1-diphenylpropan-2-yl2-(3-(acetoxymethoxy)-4-methoxypicolinamido)propanoate

To a suspension of (S)—(S)-1,1-diphenylpropan-2-yl2-(3-hydroxy-4-methoxypicolinamido)-propanoate (Cmpd 90; 100 mg, 0.230mmol) and K₂CO₃ (63.6 mg, 0.460 mmol) in acetone (4.6 mL) was addedbromomethyl acetate (33.9 μL, 0.345 mmol) at room temperature, and themixture was heated to 55° C. for 3 h and then cooled to roomtemperature. The solvent was evaporated and the resulting crude materialwas purified by flash column chromatography (SiO₂, 1→40% acetone inhexanes) to afford the title compound (94.0 mg, 80% yield) as acolorless oil: ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J=5.4 Hz, 1H), 8.22(d, J=7.9 Hz, 1H), 7.34-7.09 (m, 10H), 6.92 (d, J=5.4 Hz, 1H), 5.83 (dq,J=10.1, 6.2 Hz, 1H), 5.72 (d, J=0.7 Hz, 2H), 4.60-4.49 (m, 1H), 4.06 (d,J=10.1 Hz, 1H), 3.88 (s, 3H), 2.05 (s, 3H), 1.25 (d, J=6.1 Hz, 3H), 0.91(d, J=7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 172.33, 170.25, 162.88,160.24, 145.70, 143.91, 142.54, 141.48, 141.25, 128.76, 128.49, 128.12,128.09, 126.89, 126.65, 109.56, 89.50, 73.27, 57.92, 56.17, 48.07,20.86, 19.25, 17.73; HRMS-ESI (m/z) [M+H]⁺ calcd for C₂₄H₃₁N₂O₇,507.2131; found, 507.2125.

Example 6C: Preparation of (S)—(S)-1,1-diphenylpropan-2-yl2-(3-((isobutyryloxy)methoxy)-4-methoxypicolinamido)propanoate

To a solution of (S)—(S)-1,1-diphenylpropan-2-yl2-(3-hydroxy-4-methoxypicolinamido)-propanoate (Cmpd 90; 100 mg, 0.230mmol) in acetone (4.6 mL) were added sodium carbonate (Na₂CO₃; 73.2 mg,0.690 mmol), sodium iodide (NaI; 6.90 mg, 0.046 mmol) and chloromethyl2-ethoxyacetate (62.9 mg, 0.460 mmol). The mixture was heated to 55° C.overnight and then cooled to room temperature, and the solvent wasevaporated. The resulting residue was purified by flash columnchromatography (SiO₂, 2→30% acetone in hexanes) to afford the titlecompound (79.0 mg, 64%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ8.28 (d, J=7.9 Hz, 1H), 8.25 (d, J=5.3 Hz, 1H), 7.36-7.08 (m, 10H), 6.92(d, J=5.4 Hz, 1H), 5.83 (dq, J=10.1, 6.2 Hz, 1H), 5.79-5.69 (m, 2H),4.62-4.44 (m, 1H), 4.06 (d, J=10.1 Hz, 1H), 3.86 (s, 3H), 2.53 (hept,J=7.0 Hz, 1H), 1.25 (d, J=6.2 Hz, 3H), 1.13 (d, J=7.0 Hz, 6H), 0.91 (d,J=7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 176.22, 172.34, 162.85,160.23, 145.55, 144.16, 142.18, 141.48, 141.26, 128.76, 128.49, 128.12,128.09, 126.89, 126.65, 109.48, 89.90, 73.26, 57.93, 56.12, 48.07,33.85, 19.26, 18.68, 17.74; HRMS-ESI (m/z) ([M+H]⁺) calcd forC₃₀H₃₅N₂O₇, 535.2444; found, 535.2431.

Example A: Evaluation of Fungicidal Activity: Leaf Blotch of Wheat(Zymoseptoria tritici; Bayer Code SEPTTR)

Technical grades of materials were dissolved in acetone, which were thenmixed with nine volumes of water (H₂O) containing 110 ppm Triton X-100.The fungicide solutions were applied onto wheat seedlings using anautomated booth sprayer to run-off. All sprayed plants were allowed toair dry prior to further handling. All fungicides were evaluated usingthe aforementioned method for their activity vs. all target diseases,unless stated otherwise. Wheat leaf blotch and brown rust activity werealso evaluated using track spray applications, in which case thefungicides were formulated as EC formulations, containing 0.1% Trycol5941 in the spray solutions.

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated withan aqueous spore suspension of Zymoseptoria tritici either prior to orafter fungicide treatments. After inoculation the plants were kept in100/relative humidity (one day in a dark dew chamber followed by two tothree days in a lighted dew chamber at 20° C.) to permit spores togerminate and infect the leaf. The plants were then transferred to agreenhouse set at 20° C. for disease to develop. When disease symptomswere fully expressed on the 1^(st) leaves of untreated plants, infectionlevels were assessed on a scale of 0 to 100 percent disease severity.Percent disease control was calculated using the ratio of diseaseseverity on treated plants relative to untreated plants.

Example B: Evaluation of Fungicidal Activity: Wheat Brown Rust (Pucciniatriticina; Synonym: Puccinia recondita f. Sp. tritici; Bayer CodePUCCRT)

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated withan aqueous spore suspension of Puccinia triticina either prior to orafter fungicide treatments. After inoculation the plants were kept in adark dew room at 22° C. with 100% relative humidity overnight to permitspores to germinate and infect the leaf. The plants were thentransferred to a greenhouse set at 24° C. for disease to develop.Fungicide formulation, application and disease assessment followed theprocedures as described in the Example A.

Example C: Evaluation of Fungicidal Activity: Wheat Glume Blotch(Leptosphaeria nodorum; Bayer Code LEPTNO)

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated withan aqueous spore suspension of Leptosphaeria nodorum 24 h afterfungicide treatments. After inoculation the plants were kept in 100%relative humidity (one day in a dark dew chamber followed by two days ina lighted dew chamber at 20° C.) to permit spores to germinate andinfect the leaf. The plants were then transferred to a greenhouse set at20° C. for disease to develop. Fungicide formulation, application anddisease assessment followed the procedures as described in the ExampleA.

Example D: Evaluation of Fungicidal Activity: Apple Scab (Venturiainaequalis; Bayer Code VENTIN)

Apple seedlings (variety McIntosh) were grown in soil-less Metro mix,with one plant per pot. Seedlings with two expanding young leaves at thetop (older leaves at bottom of the plants were trimmed) were used in thetest. Plants were inoculated with a spore suspension of Venturiainaequalis 24 h after fungicide treatment and kept in a 22° C. dewchamber with 100% relative humidity for 48 h, and then moved to agreenhouse set at 20° C. for disease to develop. Fungicide formulation,application and disease assessment on the sprayed leaves followed theprocedures as described in the Example A.

Example E: Evaluation of Fungicidal Activity: Leaf Spot of Sugar Beets(Cercospora beticola; Bayer Code CERCBE)

Sugar beet plants (variety HH88) were grown in soil-less Metro mix andtrimmed regularly to maintain a uniform plant size prior to test. Plantswere inoculated with a spore suspension 24 h after fungicide treatments.Inoculated plants were kept in a dew chamber at 22° C. for 48 h thenincubated in a greenhouse set at 24° C. under a clear plastic hood withbottom ventilation until disease symptoms were fully expressed.Fungicide formulation, application and disease assessment on the sprayedleaves followed the procedures as described in the Example A.

Example F: Evaluation of Fungicidal Activity: Asian Soybean Rust(Phakopsora pachyrhizi; Bayer Code PHAKPA)

Technical grades of materials were dissolved in acetone, which were thenmixed with nine volumes of H₂O containing 0.011% Tween 20. The fungicidesolutions were applied onto soybean seedlings using an automated boothsprayer to run-off. All sprayed plants were allowed to air dry prior tofurther handling.

Soybean plants (variety Williams 82) were grown in soil-less Metro mix,with one plant per pot. Two weeks old seedlings were used for testing.Plants were inoculated either 3 days prior to or 1 day after fungicidetreatments. Plants were incubated for 24 h in a dark dew room at 22° C.and 100% relative humidity then transferred to a growth room at 23° C.for disease to develop. Disease severity was assessed on the sprayedleaves.

Example G: Evaluation of Fungicidal Activity: Barley Scald(Rhyncosporium secalis; Bayer Code RHYNSE)

Barley seedlings (variety Harrington) were propagated in soil-less Metromix, with each pot having 8 to 12 plants, and used in the test when thefirst leaf was fully emerged. Test plants were inoculated by an aqueousspore suspension of Rhyncosporium secalis 24 h after fungicidetreatments. After inoculation the plants were kept in a dew room at 22°C. with 100% relative humidity for 48 h. The plants were thentransferred to a greenhouse set at 20° C. for disease to develop.Fungicide formulation, application and disease assessment on the sprayedleaves followed the procedures as described in the Example A.

Example H: Evaluation of Fungicidal Activity: Rice Blast (Pyriculariaoryzae; Bayer Code PYRIOR)

Rice seedlings (variety Japonica) were propagated in soil-less Metromix, with each pot having 8 to 14 plants, and used in the test when 12to 14 days old. Test plants were inoculated with an aqueous sporesuspension of Pyricularia oryzae 24 h after fungicide treatments. Afterinoculation the plants were kept in a dew room at 22° C. with 100%relative humidity for 48 h to permit spores to germinate and infect theleaf. The plants were then transferred to a greenhouse set at 24° C. fordisease to develop. Fungicide formulation, application and diseaseassessment on the sprayed leaves followed the procedures as described inthe Example A.

Example I: Evaluation of Fungicidal Activity: Tomato Early Blight(Alternaria solani; Bayer Code ALTESO)

Tomato plants (variety Outdoor Girl) were propagated in soil-less Metromix, with each pot having one plant, and used when 12 to 14 days old.Test plants were inoculated with an aqueous spore suspension ofAlternaria solani 24 h after fungicide treatments. After inoculation theplants were kept in a dew room at 22° C. with 100% relative humidity for48 h to permit spores to germinate and infect the leaf. The plants werethen transferred to a growth room at 22° C. for disease to develop.Fungicide formulation, application and disease assessment on the sprayedleaves followed the procedures as described in the Example A.

Example J: Evaluation of Fungicidal Activity: Cucumber Anthracnose(Colletotrichum lagenarium; Bayer Code COLLLA)

Cucumber seedlings (variety Bush Pickle) were propagated in soil-lessMetro mix, with each pot having one plant, and used in the test when 12to 14 days old. Test plants were inoculated with an aqueous sporesuspension of Colletotrichum lagenarium 24 hr after fungicidetreatments. After inoculation the plants were kept in a dew room at 22°C. with 100% relative humidity for 48 hr to permit spores to germinateand infect the leaf. The plants were then transferred to a growth roomset at 22° C. for disease to develop. Fungicide formulation, applicationand disease assessment on the sprayed leaves followed the procedures asdescribed in the Example A.

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LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20230371516A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1.-30. (canceled)
 31. A composition comprising: a) a compound of theformula:

b) an adjuvant selected from ethoxylated synthetic alcohols, salts fromthe esters or sulfosuccinic acids, blends of mineral or vegetable oilsand combinations thereof.
 32. The composition of claim 21 wherein theadjuvant is ethoxylated vegetable oil.
 33. The composition of any ofclaims 21-22 wherein the composition further comprises a dialkyl amidefatty acid solvent.
 34. The composition of any of claims 21-23 whereinthe composition is an oil-in-water emulsion concentrate.
 35. Thecomposition of any of claims 21-24 wherein the composition furtherincludes an additional fungicide.